Arylamidoalkyl-N-hydroxyurea compounds having lipoxygenase inhibitory activity

ABSTRACT

PCT No. PCT/US92/05715 Sec. 371 Date Jan. 10, 1994 Sec. 102(e) Date Jan. 10, 1994 PCT Filed Jul. 7, 1992 PCT Pub. No. WO93/02037 PCT Pub. Date Feb. 4, 1993.The present invention provides certain (substituted carbocyclic aryl)amidoalkyl- and (substituted heterocyclic aryl)amidoalkyl-N-Hydroxy urea compounds which inhibit lipoxygenase enzyme activity and are thus useful in the treatment of allergic and inflammatory disease states.

This application is a continuation-in-part of application Ser. No.07/732,520 filed Jul. 19, 1991, now U.S. Pat. No. 5,214,204.

TECHNICAL FIELD

This invention relates to compounds having activity to inhibitlipoxygenase enzymes, to pharmaceutical compositions comprising thesecompounds, and to a medical method of treatment More particularly, thisinvention concerns certain substituted arylamidoalkyl-N-hydroxyureacompounds which inhibit leukotriene biosynthesis, to pharmaceuticalcompositions comprising these compounds, and to a method of inhibitinglipoxygenase activity and leukotriene biosynthesis.

BACKGROUND OF THE INVENTION

5-Lipoxygenase is the first dedicated enzyme in the pathway leading tothe biosynthesis of leukotrienes. This important enzyme has a ratherrestricted distribution, being found predominantly in leukocytes andmast cells of most mammals. Normally 5-lipoxygenase is present in thecell in an inactive form; however, when leukocytes respond to externalstimuli, intracellular 5-lipoxygenase can be rapidly activated. Thisenzyme catalyzes the addition of molecular oxygen to fatty acids withcis,cis-1,4-pentadiene structures, converting them to1-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonic acid, the5-lipoxygenase substrate which leads to leukotriene products, is foundin very low concentrations in mammalian cells and must first behydrolyzed from membrane phospholipids through the actions ofphospholipases in response to extracellular stimuli. The initial productof 5-lipoxygenase action on arachidonate is 5-HPETE which can be reducedto 5-HETE or converted to LTA₄. This reactive leukotriene intermediateis enzymatically hydrated to LTB₄ or conjugated to the tripeptideglutathione to produce LTC₄. LTA₄ can also be hydrolyzednonenzymatically to form two isomers of LTB₄. Successive proteolyticcleavage steps convert LTC₄ to LTD₄ and LTE₄. Other products resultingfrom further oxygenation steps have also been described in theliterature. Products of the 5-lipoxygenase cascade are extremely potentsubstances which produce a wide variety of biological effects, often inthe nanomolar to picomolar concentration range.

The remarkable potencies and diversity of actions of products of the5-lipoxygenase pathway have led to the suggestion that they playimportant roles in a variety of diseases. Alterations in leukotrienemetabolism have been demonstrated in a number of disease statesincluding asthma, allergic rhinitis, rheumatoid arthritis and gout,psoriasis, adult respiratory distress syndrome, inflammatory boweldisease, endotoxin shock syndrome, atherosclerosis, ischemia inducedmyocardial injury, and central nervous system pathology resulting fromthe formation of leukotrienes following stroke or subarachnoidhemorrhage.

The enzyme 5-lipoxygenase catalyzes the fast step leading to thebiosynthesis of all the leukotrienes and therefore inhibition of thisenzyme provides an approach to limit the effects of all the products ofthis pathway. Compounds which inhibit 5-lipoxygenase are thus useful inthe treatment of disease states such as those listed above in which theleukotrienes play an important role.

SUMMARY OF THE INVENTION

In its principal embodiment, the present invention provides certainsubstituted amidoalkyl-N-hydroxyurea and aminoalkylurea compounds whichinhibit lipoxygenase enzyme activity. The compounds are useful in thetreatment of allergic and inflammatory disease states in whichleukotrienes play a role including asthma, allergic rhinitis, rheumatoidarthritis and gout, psoriasis, adult respiratory distress syndrome,inflammatory bowel disease, endotoxin shock syndrome, ischememia inducedmyocardial injury, atherosclerosis and central nervous system pathologyresulting from the formation of leukotrienes following stroke orsubarachnoid hemorrhage.

The compounds of the present invention are of the formula ##STR1## or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of hydrogen, alkyl of from one to six carbon atoms,alkenyl of from two to six carbon atoms, cycloalkyl of from three to sixcarbon atoms, and NR² R³ where R² and R³ are independently hydrogen oralkyl of from one to six carbon atoms.

The group A is selected from the group consisting of ##STR2## wherein R⁴is selected from (a) hydrogen, (b) one, two, or three halogen atoms, (c)amino, (d) alkyl of from one to six carbon atoms, (e) alkoxy of from oneto twelve carbon atoms, (f) alkenyloxy in which the alkenyl portion isof from one to twelve carbon atoms, (g) phenoxy, optionally substitutedwith one, two, or three halogen atoms, alkyl of from one to six carbonatoms, haloalkyl of from one to six carbon atoms, alkoxy of from one tosix carbon atoms, phenylalkoxy in which the alkoxy portion is of fromone to six carbon atoms, (h) thiophenoxy, optionally substituted withone, two, or three halogen atoms, alkyl of from one to six carbon atoms,haloalkyl of from one to six carbon atoms, alkoxy of from one to sixcarbon atoms, (i) benzoyl, (j) pyridyloxy, (k) phenylsulfonyl optionallysubstiuted with halogen, and (l) phenylamino optionally substituted withhalogen.

The group R⁵ is hydrogen or phenyl optionally substituted with halogenor alkyl of from one to six carbon atoms; W is --CH₂ --, --O--, or--S--; X is --CH-- or N; Y is a valence bond or is selected fromalkylene of from one to six carbon atoms, alkenylene of from two to sixcarbon atoms, and oxyalkylene of from one to six carbon atoms; and Z isoxygen, NR⁶, or sulfur, where R⁶ is alkyl of from one to six carbonatoms or substituted or unsubstituted carbocyclic aryl.

The group B is selected from the group consisting of ##STR3## wherein R⁹is selected from hydrogen, alkyl of from one to six carbon atoms,benzyl, or thienylmethylene, and D is straight or branched chainalkylene of from one to six carbon atoms; and m is 0 or 1.

The group M is hydrogen, a pharmaceutically acceptable cation, or apharmaceutically acceptable prodrug leaving group.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a lipoxygenase inhibiting effective amount of acompound as defined above in combination with a pharmaceuticallyacceptable carrier.

In yet another aspect, the present invention provides a method ofinhibiting lipoxygenase enzyme activity in a host mammal in need of suchtreatment comprising administering a lipoxygenase inhibiting effectiveamount of a compound as defined above.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms

As used throughout this specification and the appended claims, the term"alkyl" refers to a monovalent group derived from a straight or branchedchain saturated hydrocarbon by the removal of a single hydrogen atom.Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-,sec-, iso- and tert-butyl, and the like.

The term "alkenyl" denotes a monovalent group derived from a hydrocarboncontaining at least one carbon-carbon double bond by the removal of asingle hydrogen atom. Alkenyl groups include, for example, ethenyl,propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.

The term "alkylene" denotes a divalent group derived from a straight orbranched chain saturated hydrocarbon by the removal of two hydrogenatoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene,2,2-dimethylpropylene, and the like.

The term "alkenylene" denotes a divalent group derived from a straightor branched chain hydrocaron containing at least one carbon-carbondouble bond. Examples of alkenylene include --CH═CH--, --CH₂ CH═CH--,--C(CH₃)═CH--, --CH₂ CH═CHCH₂ --, and the like.

The term "alkenyloxy" refers to an alkenyl group, as defined above,attached though an oxygen atom to the parent molecular moiety.

The terms "alkoxy" and "alkoxyl" denote an alkyl group, as definedabove, attached to the parent molecular moiety through an oxygen atom.Representative alkoxy groups include methoxyl, ethoxyl, propoxyl,butoxyl, and the like.

The term "cycloalkyl" denotes a monovalent group derived from amonocyclic or bicyclic saturated carbocyclic ting compound by theremoval of a single hydrogen atom. Examples include cyclopropyl,cyclobutyl, cycopentyl, cyclohexyl, bicyclo 2 2.1!heptanyl, and bicyclo2.2.2!octanyl.

The term "haloalkyl" denotes an alkyl group, as defined above, havingone, two, or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term "phenylalkoxy" refers to a phenyl group attached to the parentmolecular moiety through an alkoxy group, as defined above.

The term "prodrug leaving group" denotes a group which is cleaved invivo to yield the parent molecule of the structural formulae indicatedabove wherin M is hydrogen. Examples of metabolically cleavable groupsinclude --COR, --COOR, --CONRR and --CH₂ OR radicals where R is selectedindependently at each occurrence from alkyl, trialkylsilyl, carbocyclicaryl or carbocyclic aryl substituted with one or more of C₁ -C₄ alkyl,halogen, hydroxy or C₁ -C₄ alkoxy. Specific examples of representativemetabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl,methoxymethyl and trimethylsilyl groups.

Preferred Embodiments

Preferred compounds of the present invention are those having thestructure ##STR4## where the values of A, D, and M are as deemed above.Particular compounds falling within the scope of the present inventioninclude, but are not limited to:

N-hydroxy-N- (((3-phenoxyphenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N- 2-((3-phenoxyphenylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- (((3-phenylmethoxyphenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N- ((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N- ((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N'methyl-N-((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N- ((N-phenylmethyl-(4-bromophenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N-((N-thien-2-ylmethyl-(4-bromophenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N-((N-thien-2-ylmethyl-(4-bromophenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N-((N-methyl-(3-phenylmethoxyphenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N- (((4-phenoxyphenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N-(((trans-4-(4-bromophenyl)but-3-en-2-yl)amino)carbonyl)methyl!urea;

N-hydroxy-N-(((trans-4-(3-phenoxyphenyl)but-3-en-2-yl)amino)carbonyl)methyl!urea;

N-hydroxy-N-(((cis-4-(4-bromophenyl)but-3-en-2-yl)amino)carbonyl)methyl!urea;

N-hydroxy-N- 2-(((4-bromophenylacetyl)-N-methyl)amino)ethyl!urea;

N-hydroxy-N- (N-methyl-(3-phenoxyphenylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-methoxyphenylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-methoxyphenylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-butoxyphenylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- ((3-butoxyphenylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-chlorobenzoyl)amino)ethyl!urea;

N-hydroxy-N- 3-(((3-phenoxybenzoyl)amino)propyl!urea;

N-hydroxy-N- 4-((3-phenoxybenzoyl)amino)butyl!urea;

N-hydroxy-N'-methyl-N- 3-((3-phenoxybenzoyl)amino)propyl!urea;

N-hydroxy-N'-methyl-N- 2-((3-phenoxybenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3 -(3-trifluoromethylphenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(4-chlorophenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N'-methyl-N- 2-((3-(4-chlorophenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(4-methoxyphenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(3,4-dichlorophenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(3,5-dichlorophenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(4-tert-butylphenoxy)benzoyl)amino)ethyl!urea;

(R)-N-hydroxy-N- 2-((3-phenoxybenzoyl)amino)propyl!urea;

N-hydroxy-N- 3-((3-phenoxybenzoyl)amino)prop-2-yl!urea;

N-hydroxy-N- 2-((4-phenylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-phenylmethyloxybenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((5-phenoxyfuran-2-oyl)amino)ethyl!urea;

N-hydroxy-N-2-(N-methyl-((3-(4-chlorophenoxy)phenyl)methyl)amino)ethyl!urea;

N-hydroxy-N-2-(N-methyl-((3-(4-methoxyphenoxy)phenyl)ethyl)amino)ethyl!urea;

N-hydroxy-N-2-(N-methyl((3-(3,4-dichlorophenoxy)phenyl)methyl)amino)ethyl!urea;

N-hydroxy-N-2-(N-methyl-((3-(3,5-dichlorophenoxy)phenyl)methyl)amino)ethyl!urea;

N-hydroxy-N-2-(((((4-methoxy-3-phenylmethoxy)phenyl)methyl)-N-methyl)amino)ethyl!urea;

(S)-N-hydroxy-N- 2-((tert-butoxycarbonyl)amino)propyl!urea;

(R)-N-hydroxy-N- 2-((tert-butoxycarbonyl)amino)propyl!urea;

N-hydroxy-N- 2-((tert-butoxycarbonyl)amino)ethyl!urea;

N-hydroxy-N-(((3-(4-chlorophenoxy)phenyl)prop-2-enyl)amino)carbonyl)methyl!urea;

N-hydroxy-N- 2-((3-(1-methylethoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(2-methyl-prop-2-enyloxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((naphth-2-ylsulfonyl)amino)ethyl!urea;

N-hydroxy-N- 2-(((1-(4-chlorophenylmethyl)pyrrol-2-yl)carbonyl)amino)ethyl!urea;

N-hydroxy-N-2-(((3-(4-chlorophenoxy)benzoyl)-N-methyl)amino)propyl!urea;

N-hydroxy-N- 2-((2-phenoxybenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-phenoxybenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-(3-((4-bromophenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-(3-((4-fluorophenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(pyrid-2-yloxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-phenoxyphenylacetyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-n-hexyloxybenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((5-(4-chlorophenoxy)furan-2-oyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-(4-chlorothiophenoxy)thien-3-oyl)amino)ethyl!urea;

(S)-N-hydroxy-N- 2-((5-(4-chlorophenoxy)fur-2-oyl)amino)propyl!urea;

N-hydroxy-N- 2-((5-(4-chlorophenoxy)fur-2-oyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(4-chlorophenylsulfonyl)benzoyl)amino)ethyl!urea;

N-hydroxy-N- ((benzo b!furan-2-oyl)amino)ethyl!urea;

N-hydroxy-N- ((4-chlorobenzo b!thien-2-oyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-benzoylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-(1 -phenylethyloxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(1-phenylethyloxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-(((4-(1-phenylethyl)phenyl)propion-2-yl)amino)ethyl!urea;

N-hydroxy-N- 2-(((3-(1-phenylethyl)phenyl)propion-2-yl)amino)ethyl!urea;

N-hydroxy-N- 2-(((2-(1-phenylethyl)phenyl)propion-2-yl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-phenoxyphenoxyacetyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-phenoxyphenoxyacetyl)amino)ethyl!urea;

N-hydroxy-N- 2-((2-phenoxyphenoxyacetyl)amino)ethyl!urea;

N-hydroxy-N'-methyl-N- 2-((quinolin-2-oyl)amino)ethyl!urea;

N-hydroxy-N- 2-((quinolin-2-oyl)amino)ethyl!urea;

N-hydroxy-N-2-(((3-(6-methoxynaphth-2-yl)prop-2-en-2-yl)carbonyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-phenylpropionyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(4-n-butoxyphenyl)prop-2-enoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(3-n-butoxyphenyl)prop-2-enoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(2-n-butoxyphenyl)prop-2-enoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((2-(6-methoxynaphth-2-yl)propionyl)amino)ethyl!urea;

N-hydroxy-N- 2-((2-(4-(2-methylpropyl)phenyl)propionyl)amino)ethyl!urea;

N-hydroxy-N-2-((2-(2,6-dichlorophenylamino)phenylacetyl)amino)ethyl!urea;

N-hydroxy-N- 2-((2-phenylthiazol-4-oyl)amino)ethyl!urea;

(d,l)-N-hydroxy-N- 3-((tert-butyoxycarbonyl)amino)prop-2-yl!urea;

N-hydroxy-N- 3-((5-(4-fluorophenoxy)furan-2-oyl)amino)prop-2-yl!urea;

N-hydroxy-N- 2-((2-(1-phenylethyloxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- 4-((5-(4-fluorophenoxy)furan-2-oyl)amino)but-2-yl!urea;

N-hydroxy-N- 2-((2-phenoxybenzoyl)amino)ethyl!urea;

N-hydroxy-N-2- (3-(4-bromophenyl)propenoyl)amino!ethyl urea;

N-hydroxy-N-2- (3-phenylpropenoyl)amino!ethyl urea;

(R)-N-hydroxy-N- 2-(3-(4-bromophenyl)propenoyl)amino!propyl urea;

(d,l)-N-hydroxy-N- 3-(3-(4-bromophenyl)propenoyl)amino !prop-2-yl urea;

N-hydroxy-N- 2-(3-(4-bromophenyl)propanoyl)amino!ethyl urea;

N-hydroxy-N-2- (3-(3-(4-chlorophenoxy)phenyl)propynoyl)amino!ethyl urea;

N-hydroxy-N-2- N"-benzyloxycarbonyl-((3-phenoxyphenyl)methyl)amino!ethylurea;

N-hydroxy-N-2- (3-phenoxyphenyl)methyl)amino!ethyl urea;

N-hydroxy-N-2-(3-(3-(4-chlorophenoxy)phenyl)-trans-propenoyl)amino!ethyl urea;

N-hydroxy-N-2- (3-(3-butyloxyphenyl)-trans-propenoyl)amino!ethyl urea;

N-hydroxy-N-2-(3-(4-chlorophenoxy)phenyl)-3-methyl-transpropenoyl)amino!ethyl urea;

N-hydroxy-N-2- (3-(4-bromophenyl)-2-methyl-trans-propenoyl)amino!ethylurea;

N-hydroxy-N-2-(3-(4-chlorophenoxy)phenyl)-2-methyl-transpropenoyl)amino!ethyl urea;

N-hydroxy-N-2-(2-(3-(4-ethyloxyphenoxy)phenyl)-trans-cyclopropyl)carbonyl amino!ethylurea;

(S)-N-hydroxy-N- 2-((2-(3-phenoxyphenyloxy)acetyl)amino)propyl!urea;

N-hydroxy-N- 2-((2-(3-phenoxyphenyloxy)propionyl)amino)ethyl!urea;

(d,l)-N-hydroxy-N-3-(2-(3-(4-chlorophenoxy)phenyl)acetylamino)prop-2-yl!urea;

N-hydroxy-N- 3-(3-(3-(4-chlorophenoxy)phenyl)propionyl)amino!prop-2-ylurea; and

N-hydroxy-N-5- (3-phenoxybenzoyl)amino!-pent-3-yn-2-yl urea.

Preferred compounds of the present invention are

N-hydroxy-N- 2-((5-(4-chlorophenoxy)fur-2 -oyl)amino)ethyl!urea;

(R)-N-Hydroxy-N- 2-((5-(4-chlorophenoxy)fur-2-oyl)amino)propyl!urea;

(S)-N-hydroxy-N- 2-((5-(4-chlorophenoxy)fur-2-oyl)amino)propyl!urea;

(R)-N-hydroxy-N- 3-((5-(4-fluorophenoxy)furan-2-oyl)amino)prop-2-yl!urea

(S)-N-hydroxy-N- 3-((5-(4-fluorophenoxy)furan-2-oyl)amino)prop-2-yl!urea

(R)-N-hydroxy-N-3-((5-(4-fluorothiophenoxy)furan-2-oyl)amino)prop-2-yl!urea;

(S)-N-hydroxy-N-3-((5-(4-fluorothiophenoxy)furan-2-oyl)amino)prop-2-yl!urea;

N-hydroxy-N- 2-((5-(4-methyl phenoxy)furan-2 -oyl)amino)ethyl!urea;

N-hydroxy-N- 2-((3-(4-chlorophenoxy)benzoyl)amino)ethyl!urea;

N-hydroxy-N- (((3-phenoxyphenyl)amino)carbonyl)methyl!urea;

N-hydroxy-N- 2-((3-phenoxyphenylbenzoyl)amino)ethyl!urea;

N-hydroxy-N- 2-((4-butoxyphenylbenzoyl)amino)ethyl!urea; and

N-hydroxy-N- 2-((5-(4-chlorophenoxy)furan-2-oyl)amino)ethyl!urea;

with the compound N-hydroxy-N-3-((5-(4-fluorophenoxy)furan-2-oyl)amino)prop-2-yl!urea and itsindividual enantiomers and mixtures thereof being most preferred.

Certain compounds of this invention exist in stereoisomeric forms byvirtue of the presence of one or more chiral centers. The presentinvention contemplates all such stereoisomers, including R- andS-enantiomers, diastereomers, and mixtures thereof as falling within thescope of the invention. If a particular enantiomer is desired, it may beprepared by chiral synthesis or by derivatization with a chiralauxiliary where the resulting diastereomeric mixture is separated andthe auxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group suchas amino or an acidic functional group such as carboxyl diastereomericsalts are formed with an appropriate optically active acid or base,followed by resolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means well known in the an andsubsequent recovery of the pure enantiomers.

Certain compounds of the present invention may contain a basicfunctional group such as amino, alkylamino, or dialkylamino and are thuscapable of forming salts with pharmaceutically acceptable acids. Theterm "pharmaceutically acceptable salts" in this respect, refers to therelatively non-toxic, inorganic and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate,mesylate, glucoheptonate, lactiobionate, laurylsulphonate salts and thelike. (See, for example S. M. Berge, et al., "Pharmaceutical Salts," J.Pharm. Sci., 66:1-19 (1977) which is incorporated herein by reference.)

In other cases, the compounds may contain one or more acidic functionalgroups such as carboxyl and the like and are capable of forming saltswith pharmaceutically acceptable bases. The term "pharmaceuticallyacceptable salts" in these instances refers to the relatively non-toxic,inorganic and organic base addition salts of compounds of the presentinvention. These salts can be likewise prepared in situ during the finalisolation and purification of the compounds or by separately reactingthe purified compound in its free acid form with a suitable base such asthe hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia, or an organic primary, secondary, ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, and the like. (See, forexample S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci.,66:1-19 (1977) which is incorporated herein by reference.)

Lipoxygenase Inhibition Determination

Assays to determine 5-lipoxygenase inhibitory activity of representativecompounds of the present invention were performed in 200 mL incubationscontaining the 20,000×g supernatant from 1.5 million homogenized HWBL-1cells and various concentrations of the test compound. Reactions wereinitiated by addition of radiolabeled arachidonic acid and terminated byacidification and ether extraction. Reaction products were separatedfrom nonconverted substrate by thin layer chromatography and measured byliquid scintillation spectroscopy. All incubations are performed intriplicate. Inhibition of 5-lipoxygenase activity was calculated as theratio of the amount of product formed in the presence and absence ofinhibitor. IC₅₀ values (concentration of compound producing 50% enzymeinhibition) were calculated by linear regression analysis of percentageinhibition versus log inhibitor concentration plots. (Dyer, R. D.;Haviv, F.; Hanel, A. M.; Bornemier, D. A.; Carter, G. W. Fed. Proc.,Fed. Am. Soc. Exp. Biol. 1984, 43, 1462A). Results for compounds of theforegoing examples are indicated in Table 1.

                  TABLE 1    ______________________________________    In Vitro Inhibitory Potencies of Compounds of this Invention    Against 5-Lipoxygenase from HWBL-1 20,000xg Supernatant    Example      IC.sub.5O  (10.sup.-6  M)    ______________________________________     1           0.48     2           0.23     3           0.87     4           5.8    5,step 2     6.3    5, step3     7.3    9            2.8    10           3.5    11           6.6    12           0.73    13           0.83    14           1.8    15           0.64    16           1.9    17           5.0    18           0.25    19           0.26    20           4.5    21           0.07    22           0.33    24           0.29    25           0.43    26           0.16    27           0.76    28           0.23    29           0.30    30           0.34    31           0.47    32           0.21    33           0.61    34           0.38    35           0.22    36           0.13    37           0.10    38           0.20    39           0.31    40           0.15    41           1.6    46           0.29    47           0.23    48           1.1    49           0.29    50           5.8    51           0.24    52           0.16    53           0.44    54           0.15    55           1.0    56           0.22    57           0.29    58           0.11    59           0.10    60           0.28    61           0.16    62           0.91    63           1.0    64           2.1    65           0.22    66           0.25    67           0.35    69           0.39    72           0.11    75           0.1    76           1.0    77           0.39    82           5.0    83           0.44    84           0.93    85           0.29    87           0.37    88           0.28    ______________________________________

Inhibition of Leukotriene Biosynthesis

Inhibition of the biosynthesis of leuktrienes in vivo after oraladministration of compound was determined using a rat peritonealanaphylaxis model in a similar manner as that described by Young andcoworkers (Young, P. R.; Dyer, R. D.; Carter, G. W. Fed. Proc., Fed. Am.Soc. Exp. Biol. 1985, 44, 1185). In this model rats were injectedintraperitoneally (ip) with rabbit antibody to bovine serum albumin(BSA) and three hours later injected ip with BSA to induce anantgen-antibody response. Rats were sacrificed 15 minutes after thischallenge and the peritoneal fluids were collected and analyzed forleukotriene levels. Test compounds were administered by gavage one hourprior to the antigen challenge. Percent inhibition values weredetermined by comparing the treatment group to the mean of the controlgroup. From the results of this assay it is demonstrated that compoundsof this invention are orally effective in preventing the in vivobiosynthesis of leukotrienes. The results are presented in Table 2.

                  TABLE 2    ______________________________________    % Inhibition of Leukotrienes           Oral Dose   Oral Dose   Oral Dose    Example           at 30 μmol/kg                       at 50 μmol/kg                                   at 100 μmol/kg    ______________________________________    2      --          --          84    19     --          --          63    21     --          --          95    26     --          --          99    32     --          --          90    35     --          --          15    37     --          --          80    38     --          --          86    40     --          --          76    55     --          --          83    56     --          --          85    60     --          --          84    87     --          --          60    23     57          --          --    36     78          --          --    51     47          --          --    52     19          --          --    53     33          --          --    54     11          --          --    63     52          --          --    64     92          --          --    73     53          --          --    88     84          --          --    58     --          81          --    61     --          60          --    ______________________________________

Preparation of Compounds of this Invention

The compounds of this invention can be prepared from the appropriatestarting substituted aryl amines or acids as is illustrated in SchemesI-III. The synthesis of the aniline-derived amide-linked N-hydroxy ureasof this invention begins with the acylation of the desired aryl amine(I) with bromoacetyl bromide. The resulting α-halo amide was thentreated with anhydrous sodium acetate in refluxing absolute ethanol toprovide the α-acetoxy amide which was convened to the correspondingalcohol (II) with aqueous sodium hydroxide at ambient temperature. Thealcohol was convened to the diprotected N-hydroxyl amine (III) utilizinga modified Mitsunobu procedure (Maurer, P. J.; Miller, M. J. J. Am.Chem. Soc., 1982, 104, 3096) with N,O-bis-t-butyloxycarbonylhydroxylamine (Carpino, L. A.; et. al. J. Am. Chem. Soc., 1959, 81,955). Deprotection provides the hydroxylamine intermediate which isconvened to the desired N-hydroxy urea by treatment with trimthylsilylisocyanate in an anhydrous, aprotic solvent. ##STR5##

The aryl acid (V) derived amide-linked N-hydroxy ureas are preparedaccording to the sequence described in Scheme II. Conversion of thestarting acid to the corresponding β-hydroxy amide (VI) was achievedthrough acylation of the corresponding acid chloride with ethanol amine.The hydroxyamide was converted via a modified Mitsunobu process toobtain the diprotected N-hydroxyl amine (VII) which was deprotected andconverted to the desired aryl acid derived amide-linked N-hydroxy urea(VIII) as described in Scheme I. ##STR6##

Alternately, compounds of this invention can be prepared by the generalmethod outlined in Scheme III. A BOC-protected aminoalcohol (IX) isconverted to the corresponding N-hydroxyurea (XII) by oxidizing to thealdehyde, oxime formation, reduction to the hydroxylamine, and treatmentwith TMSNCO. The N-hydroxyurea is then selectively O-acylated to give(XIII) which is deprotected under acidic conditions (TFA) andneutralized to permit the O- to N-rearrangement providing the desiredhydroxyurea products (XIV). ##STR7##

Synthesis of amine linked N-hydroxy ureas is outlined in Scheme IV. Thesequence was initiated by carrying out a reductive amination between thedesired aryl aldehyde (XV) and the appropriate aminoalcohol (X). Theresulting aryl aminoalcohol (XVI) was then transformed into the desiredamino-linked N-hydroxy urea (XVIII) following the previously describedmodified mitsunobu, deprotection, and isocyanate treatment as describedin Scheme I. ##STR8##

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.The term "parenteral" administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carders, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like, Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in rum, may depend upon crystal size andcrystalline form. Alteratively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers, or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the anto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about5 to about 20 mg of active compound per kilogram of body weight per dayare administered orally to a mammalian patient. If desired, theeffective daily dose may be divided into multiple doses for purposes ofadministration, e.g. two to four separate doses per day.

EXAMPLE 1 Preparation of N-Hydroxy-N-(((3-phenoxyphenyl)amino)carbonyl)methyl!urea

A solution of m-phenoxyaniline (6.12 g, 32.4 mmol) and triethylamine(3.7 mL, 42.1 mmol) in anhydrous ether (100 mL) was cooled to -23° C.under a nitrogen atmosphere. To this solution was added bromoacetylbromide (6.8 mL, 48.6 mmol) in anhydrous ether (30 mL). The reaction wasstirred for 1 h at -23° C. and diluted with ethyl acetate (500 mL). Theresulting solution was washed sequentially (1×, 10% aqueous HCl; 1×saturated NaHCO₃ ; 1× brine), dried (Na₂ SO₄), filtered, andconcentrated in vacuo to provide the α-bromoamide (10.05 g, 101%) as ared-brown solid which was best utilized without further purification.

The α-bromoamide (5.39 g, 17.6 mmol) was heated at reflux in 95% ethanolwith sodium acetate (4.33 g, 52.8 mmol) and checked for completion viathin layer chromatography. The reaction mixture was cooled and treatedwith aqueous sodium hydroxide (1.06 g, 26.4 mmol). The volatiles wereremoved in vacuo anti the resulting slurry was diluted with brine (500mL) and extracted (2×, EtOAc). The combined organic extracts were washed(1×, brine), dried (Na₂ SO₄), filtered, and concentrated in vacuo toprovide the α-hydroxy amide as a thick, dark brown, oil. Chromatographicpurification (100 g silica gel, 20% EtOAc:CHCl₃) provided a light brownsolid(3.46 g, 81%) which was recrystallized from EtOAc:Hexanes toprovide an analytical sample. m.p. 152.5°-154° C.

The resulting hydroxy amide (0.50 g, 2.06 mmol), triphenylphosphine(0.70 g, 2.67 mmol), and N,O-bis-t-butyloxycarbonyl hydroxylamine (0.56g, 2.47 mmol) were dissolved in anhydrous tetrahydrofuran (THF) (5 mL)and cooled to 0° C. To this solution was added diethylazodicarboxylate(DEAD)(0.42 mL, 2.67 mmol) in anhydrous THF (3 mL). The reaction wasstirred at 0° C. for 1 h and the volatiles removed in vacuo.Chromatographic purification (100 g silica gel, 25% EtOAc:Hex) providedthe bis-protected α-N-hydroxylamino amide (0.503 g, 53%) as a colorlessfoam.

The deprotection was carried out by dissolving the hydroxylamino amide0.463 g, 1.01 mmol) in glacial acetic acid (4 mL) and adding 6N aqueoushydrochloric acid (1.7 mL, 10.1 mmol) and stirring for one hour atambient temperature. The pH of the reaction was adjusted to -10 by firstadding 15% aqueous sodium hydroxide to pH=7, then adding saturatedsodium carbonate until the desired pH was achieved. The resulting cloudyaqueous solution was extracted (2×, EtOAc). The combined organicextracts were washed (1×, brine), dried (Na₂ SO₄), filtered, andconcentrated in vacuo to provide the deprotected hydroxyl amine (0.26 g,100%). Without further purification, hydroxyl amine was dissolved inanhydrous THF (5 mL) and treated with trimethylsilyl isocyanate (273mmol, 2.0 mmol). The reaction was judged complete by thin layerchromatography after 1 h and quenched by adding excess aqueoushydrochloric acid (5 mL 10% HCl). The two-phased solution waspartitioned between brine and EtOAc. The organic layer was drawn off andwashed (1×, brine), dried (Na₂ SO₄), filtered, and concentrated in vacuoto provide the title compound. Recrystallization from acetone/methanolprovided an analytical sample (0.15 g, 49%). m.p. 182.5°-184° C. withdecomposition; ¹ H NMR (300 MHz, DMSO-d₆); 9.87 (1H, s), 9.46 (1H, s),7.27-7.43 (5H, m), 7.15 (1H, t, J=7 Hz), 7.03 (2H, t, J=7 Hz), 6.73 (2H,s), 6.25 (1H, m), 6.40 (2H, s), 4.11 (2H, s); MS (M+H)⁺ =302, (M+NH₄)⁺=319. Analysis calc'd for C₁₅ H₁₅ N₃ O₄ : C, 59.80 H, 5.02; N, 13.95;Found: C, 59.85; H, 5.08; N, 14.00.

EXAMPLE 2 Preparation of N-Hydroxy-N-2-((3-phenoxyphenylbenzoyl)amino)ethyl!urea

A solution of m-phenoxybenzoic acid (6.06 g, 28.29 mmol)in anhydrous THF(90 mL) was cooled to 0° C. under a nitrogen atmosphere. To thissolution was added a catalytic amount of dimethylformamide (DMF) (3drops) and oxalyl chloride (4.94 mL, 56.58 mmol) in dichloromethane (20mL). After complete addition, the cooling bath was removed, the reactionwas stirred for 1 h, the volatiles were removed in vacuo, and theresidue was dissolved in chloroform (100 mL) and concentrated in vacuo(three cycles) to provide the corresponding acid chloride which was usedwithout further purification.

To a solution of ethanol amine (3.42 mL, 56.58 mmol) and triethylamine(5.92 mL, 47.44 mmol) in dichloromethane (90 mL) was added the acidchloride in dichloromethane (20 mL). The reaction was stirred at ambienttemperature for 0.5 h and poured into 10% aqueous HCl. The resultingtwo-phased solution was extracted (2×, dichloromethane). The combinedorganic extracts were washed sequentially (1×, saturated NaHCO₃ ; 1×,brine), dried (MgSO₄), filtered and concentrated in vacuo to provide thecorresponding amide (8.20 g, 113%) as a thick oil which was used withoutfurther purification.

Following the procedure for the conversion of Example 1 but using amideprepared above (3.04 g, 14.19 mmol), the desired di-protectedN-hydroxylamine (3.85 g, 57%) was obtained after chromatographicpurification (250 g silica gel, 20% EtOAc: Hex).

Deprotection of the di-protected N-hydroxylamine (11.94 g, 25.2 mmol)and treatment of the resulting N-hydroxylamine with TMSNCO as describedabove provided the title compound (3.55 g, 45%) after recrystallizationfrom methanol:EtOAc. m.p. 182.5°-184° C. with decomposition; ¹ H NMR(300 MHz, DMSO-d₆); 9.82 (1H, s), 8.52 (1H, t, J=5 Hz),7.61 (1H, dt,J=8,1,1), 7.38-7.52 (4H, m), 7.18 (2H, m), 7.03 (2H, dq, J=7,1,1,1, Hz),6.33 (2H, s), 3.37-3.53 (4H, m); MS (M+H)⁺ =316, (M+NH₄)⁺ =333. Analysiscalc'd for C₁₆ H₁₇ N₃ O₄ : C, 60.95 H, 5.43; N, 13.33; Found: C, 60.90;H, 5.45; N, 13.31.

EXAMPLE 3 Preparation of N-Hydroxy-N-(((3-phenylmethoxyphenyl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing 3-benzyloxyaniline in lieu of 3-phenoxyaniline.m.p. 177°-178° C. with decomposition; ¹ H NMR (300 MHz, DMSO-d₆); 9.82(1H, s), 8.52 (1H, t, J=5 Hz),7.61 (1H, dt, J=8,8,1,1,1), 7.38-7.52 (4H,m), 7.18 (2H, m), 7.03 (2H, dq, J=7,7,1,1,1, Hz), 6.33 (2H, s),3.37-3.53 (4H, m); MS (M+H)⁺ =316, (M+NH₄)⁺ =333. Analysis calc'd forC₁₆ H₁₇ N₃ O₄ C, 60.95 H, 5.43; N, 13.33; Found: C, 60.90; H, 5.45; N,13.31.

EXAMPLE 4 Preparation of N-Hydroxy-N-((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea

Step 1: Preparation of N-Methyl 4-phenoxyaniline

A solution of 4-phenoxyaniline (10 g, 54.0 mmol) and ethyl formate (22mL, 270 mmol) in toluene (200 mL) were heated at reflux for 18 h and thevolatiles were removed in vacuo to provide the corresponding formamidederivative. The resulting oil was dissolved in anhydrous THF (115 mL)and added in a dropwise fashion to a suspension of lithium aluminumhydride (2.05 g, 108 mmol) in THF; the addition rate was adjusted tomaintain a steady reflux. The reaction was refluxed for 1 h aftercomplete addition of the formamide, cooled to ambient temperature, andquenched by the sequential addition of H₂ O (2.05 mL), 15% aqueous NaOH(2.05 mL), and H₂ O (6.15 mL). The resulting slurry was stirred for 1 hand filtered through a celite pad. The filtrate was dried (Na₂ SO₄),filtered and concentrated in vacuo to provide the title aniline as anoil which was employed without further purification. ¹ H NMR (300 MHz,CDCl₃); 7.23-7.31 (2H, m), 6.90-7.03 (5H, m), 6.60(2H, d, J=9 Hz),ca.3.62 (1H, br s), 2.83(3H, s); MS (M+H)⁺ =200, (M+NH₄)⁺ =217.

Step 2: Preparation of N-Hydroxy-N-((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing the 4-phenoxyaniline, prepared in step 1, abovein lieu of 3-phenoxyaniline. m.p. 147°-148° C.; ¹ H NMR (300 MHz,DMSO-d₆); 9.02 (1H, s), 7.43 (2H, t, J=7.5 Hz),7.34 (2H, t, J=7.5 Hz),7.18 (1H, t, J=7 Hz), 7.05 (4H, br t, J=7.5 Hz), 6.27 (2H, s), 3.87 (2H,br s), 3.16 (3H, br s); MS (M+H)⁺ =316, (M+NH₄)⁺ =333. Analysis calc'dfor C₁₆ H₁₇ N₃ O₄ : C, 60.95 H, 5.43; N, 13.33; Found: C, 60.62; H,5.48; N, 13.24.

EXAMPLE 5 Preparation of N-Hydroxy-N-((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea andN-Hydroxy-N'methyl-N-((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea

Step 1: Preparation of N-Methyl-3-phenoxyaniline

The title compound was obtained following the procedures described inExample 4, step 1, but employing 3-phenoxyaniline in lieu of4-phenoxyaniline. ¹ H NMR (300 MHz, CDCl₃); 7.25-7.37(2H, m), 7.00-7.14(4H, m), 6.27-6.38(3H, m),ca. 3.73 (1H, br s), 2.80(3H, s); MS (M+H)⁺=200, (M+NH₄)⁺ =217.

Step 2; Preparation of N-Hydroxy-N-((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing the product of step 1, above. m.p. 109.5°-112°C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.23 (1H, s), 7.39-7.47 (3H,m),7.02-7.22 (6H, m), 6.28 (2H, s), 3.92 (2H, br s), 3.18 (3H, br s); MS(M+H)⁺ =316, (M+NH₄)⁺ =333. Analysis calc'd for C₁₆ H₁₇ N₃ O₄ : C, 60.95H, 5.43; N, 13.33; Found: C, 60.68; H, 5.44; N, 13.30.

Step 3: Preparation of N-Hydroxy-N'-methyl-N-((N-methyl-(3-phenoxyphenyl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described instep 2, above but employing N-methyl isocyanate (Me-NCO) in lieu ofTMSNCO to provide the title compound as an amorphous solid. ¹ H NMR (300MHz, DMSO-d₆); 9.18 (1H, s), 7.39-7.47 (3H, m),6.93-7.22 (6H, m), 6.79(1H, br q, J=5 Hz), 3.93 (2H, br s), 3.18 (3H, br s), 2.58 (3H, d, J=5Hz); MS (M+H)⁺ =330, (M+NH₄)⁺ =347. Analysis calc'd for C₁₇ H₁₉ N₃ O₄(0.50 H₂ O): C, 60.34 H, 5.96; N, 12.41; Found: C, 60.85; H, 5.77; N,12.05.

EXAMPLE 6 Preparation of N-Hydroxy-N-((N-phenylmethyl-(4-bromophenyl)amino)carbonyl)methyl!urea

Step 1: Preparation of N-Benzyl 4-bromoaniline

A solution of BH₃ THF complex (54.4 mL, 54.4 mmol) was added slowly to asolution of N-benzoyl-4-bromoaniline (5.04 g, 18.3 mmol) in anhydrousTHF. The resulting solution was slowly brought to reflux and maintainedat reflux for 1.5 h. After cooling to ambient temperature, 1M HCl inmethanol (54 mL) was added and the resulting mixture heated at refluxfor 1 h. The reaction was cooled, poured into 10% HCl, and extracted(1×, Et₂ O). The aqueous layer was basified to pH˜12 by addingconcentrated ammonium hydroxide and extracted (2×, EtOAc). The combinedorganic extracts were washed (1×, brine), dried (Na₂ SO₄), filtered, andconcentrated in vacuo to provide the benzyl bromoaniline as a waxy brownsolid. Chromatographic purification (150 g silica gel, 10% EtOAc:Hex)provided the product (2.7 g, 56%) as a light red solid. m.p. 49° C.; ¹ HNMR (300 MHz, CDCl₃); 7.25-7.39 (5H, m), 7.23(2H, d, J=9 Hz), 6.50 (2H,d, J=9 Hz), 4.31 (2H, d, J=5 Hz), 4.18 (1H, br s); MS (M+H)⁺ =262/264.

Step 2: Preparation of N-Hydroxy-N-((N-phenylmethyl-(4-romophenyl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing the product from step 1, above in lieu of3-phenoxyaniline. m.p. softens at 86° C. and melts at 88°-89° C.; ¹ HNMR (300 MHz, DMSO-d₆); 9.31 (1H, s), 7.56 (2H, d, J=8 Hz), 7.13-7.32(7H, m), 6.31 (2H, s), 4.86 (2H, br s), 3.92 (2H, br s); MS (M+H)⁺=378/380, (M+NH₄)⁺ =395/397. Analysis calc'd for C₁₆ H₁₆ N₃ O₃ Br(0.50H₂ O): C, 49.62 H, 4.42; N, 10.85; Found: C, 49.93; H, 4.42; N, 10.85.

EXAMPLE 7 Preparation of N-Hydroxy-N-((N-thien-2-ylmethyl-(4-bromophenyl)amino)carbonyl)methyl!ure

The title compound was obtained following the procedures described inExample 1, but employing N-(2-thienyl)methyl-4-bromoaniline (prepared asdescribed in example 6, step 1 above from the corresponding amide of4-bromoaniline) in lieu of 3-phenoxyaniline. m.p. 94°-98° C.; ¹ H NMR(300 MHz, DMSO-d₆); 9.31 (1H, s), 7.61 (2H, d, J=9 Hz), 7.42 (1H, dd,J=5,1 Hz), 7.13 (2H, d, J=9 Hz),6.90 (1H, dd, J=5,3 Hz), 6.83 (1H, brs), 6.31 (2H, s), 4.96 (2H, br s), 3.86 (2H, br s); MS (M+H)⁺ =384/386,(M+NH₄)⁺ =401/403. Analysis calc'd for C₁₄ H₁₄ N₃ O₃ BrS(0.50 H₂ O): C,42.76 H, 3.84; N, 10.68; Found: C, 43.11; H, 3.76; N, 10.25.

EXAMPLE 8 Preparation of N-Hydroxy-N'-methyl-N-((N-thien-2-ylmethyl-(4-bromophenyl)amino)-carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 7, but employing Me-NCO in lieu of TMS-NCO. m.p. 76°-79.5° C.; ¹H NMR (300 MHz, DMSO-d₆); 9.24 (1H, s), 7.61 (2H, d, J=9 Hz), 7.42 (1H,dd, J=5,1 Hz), 7.13 (2H, d, J=9 Hz),6.90 (1H, dd, J=5,3 Hz), 6.83 (1H,br s), 4.98 (2H, br s), 3.84 (2H, br s), 2.57 (3H, d, J=5 Hz); MS (M+H)⁺=398/400, (M+NH₄)⁺ =415/417. Analysis calc'd for C₁₅ H₁₆ N₃ O₃ BrS(0.25H₂ O): C, 44.73; H, 4.13; N, 10.43; Found: C, 45.28; H, 4.34; N, 9.66.

EXAMPLE 9 Preparation of N-Hydroxy-N-((N-methyl-(3-phenylmethoxyphenyl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing N-methyl-3-benzyloxyaniline (prepared from thecorresponding aniline as described in example 3) in lieu of3-phenoxyaniline. m.p. 162°-163° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.22(1H, s), 7.33-7.50 (6H, m), 6.98-7.05 (2H, m), 6.91 (2H, br d, J=7.5Hz), 6.28 (2H, s), 5.13 (2H, s), 3.91 (2H, br s), 3.07 (3H, s); MS(M+H)⁺ =330. Analysis calc'd for C₁₇ H₁₉ N₃ O₄ (0.25 H₂ O): C, 61.16; H,5.89; N, 12.58; Found: C, 61.36; H, 5.86; N, 12.54.

EXAMPLE 10 Preparation of N-Hydroxy-N-(((4-phenoxyphenyl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing 4-phenoxyaniline in lieu of 3-phenoxyaniline.m.p. 189.5°-190.5° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.72 (1H, s), 9.53(1H, s),8.52 (1H, t, J=5 Hz),7.64 (2H, d, J=9), 7.36 (2H, dd, J=8, 9Hz), 7.17 (1H, t, J=9 Hz), 6.94 (4H, d, J=9 Hz), 6.42 (2H, s), 4.17 (2H,s); MS (M+H)⁺ =302, (M+NH₄)⁺ =319. Analysis calc'd for C₁₅ H₁₅ N₃ O₄ :C, 59.80; H, 5.02; N, 13.95; Found: C, 59.74; H, 5.01; N, 13.87.

EXAMPLE 11 Preparation of N-Hydroxy-N-(((trans-4-(4-bromophenyl)but-3-en-2-yl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing trans-2-amino-4-(4-bromophenyl)but-3-ene inlieu of 4-phenoxyaniline. The starting amine was prepared according tothe method of Dellaria (Dellaria, J. F.; Sallin, K. J. TetrahedronLett.1990, 31, 2661) m.p. 171°-172° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.42 (1H,s), 7.76 (1H, d, J=8 Hz), 7.52 (2H, d, J=8 Hz), 7.37 (2H, d, J=8 Hz),6.42-6.48 (2H, m), 6.31 (1H, dd, J=16, 5.5 Hz), 4.53 (1H, sextet, J=6.5Hz), 3.97(2H, s), 1.24 (3H, d, J=6.5 Hz); MS (M+H)⁺ =342/344, (M+NH₄)⁺=359/361. Analysis calc'd for C₁₃ H₁₆ N₃ O₃ Br: C, 45.63; H, 4.71; N,12.28; Found: C, 45.89; H, 4.70; N, 11.61.

EXAMPLE 12 Preparation of N-Hydroxy-N-(((trans,4-(3-phenoxyphenyl)but-3-en-2-yl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing trans-2-amino-4-(3-phenoxyphenyl)but-3-ene inlieu of 4-phenoxyaniline. The starting amine was prepared according tothe method of Dellaria (Dellaria, J. F.; Sallin, K. J. Tetrahedron Lett.1990, 31, 2661). m.p. 150°-151° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.40(1H, s), 7.74 (1H, d, J=7.5 Hz), 7.30-7.42 (3H, m), 7.10-7.22 (2H, m),6.97-7.07 (3H, m), 6.88 (1H, dd, J=8, 2 Hz), 6.47 (1H, d, J=15.5 Hz),6.43 (2H, s), 6.27 (1H, dd, J=15.5, 6 Hz),4.53 (1H, sextet, J=6.5 Hz)3.97(2H, s), 1.24 (3H, d, J=6.5 Hz); MS (M+H)⁺ =356, (M+NH₄)⁺ =373.Analysis calc'd for C₁₉ H₂₁ N₃ O₄ : C, 64.21; H, 5.96; N, 11.82; Found:C, 64.29; H, 6.04; N, 11.80.

EXAMPLE 13 Preparation of N-Hydroxy-N-(((cis-4-(4-bromophenyl)but-3-en-2-yl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employing cis-2-amino-4-(3-phenoxyphenyl)but-3-ene inlieu of 4-phenoxyaniline. The starting amine was prepared according tothe method of Dellaria (Dellaria, J. F.; Sallin, K. J. Tetrahedron Lett.1990, 31, 2661) m.p. 142°-143° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.37 (1H,s), 7.78 (1H, d, J=7.5), 7.42 (1.25H, AB, J=8.5 Hz), 7.37 (1.25H, AB,J=8.5 Hz), 7.10-7.18 (2H, m), 7.04 (1.5H, d, J=8.0 Hz), 6.87-6.95 (2H,m), 6.41 (2H, s), 6.38 (1H, d, J=12 Hz), 5.59 (1H, dd, J=12, 10 Hz),4.83 (1H, br sextet, J=6.5 Hz) 3.90(2H, s), 1.15 (3H, d, J=6.5 Hz); MS(M+H)⁺ =356, (M+NH₄)⁺ =373. Analysis calc'd for C₁₉ H₂₁ N₃ O₄ : C,64.21; H, 5.96; N, 11.82; Found: C, 63.81; H, 5.87; N, 11.61.

EXAMPLE 14 Preparation of N-Hydroxy-N-2-(((4-bromophenylacetyl)-N-methyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 4-bromophenylacetate in lieu of3-phenoxybenzoate and N-methylethanolamine in lieu of ethanolamine. m.p.134°-135° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.48 (0.5H, s), 9.13 (0.5H,s), 7.46 (2H, d, J=8 Hz), 7.16 (2H, d, J=8 Hz), 7.37 (2H, d, J=8 Hz),6.38 (1H, s), 6.29 (1H, s), 3.68 (2H, d J=13.5 Hz), 3.50 (2H, dd,J=13.5,4.5 Hz), 3.44 (2H, s), 3.0 (1.5H, s), 2.8 (1.5H, s); MS (M+H)⁺=330/332, (M+NH₄)⁺ =347/349. Analysis calc'd for C₁₂ H₁₆ N₃ O₃ Br: C,43.65; H, 4.88; N, 12.73; Found: C, 44.02; H, 4.94; N, 12.59.

EXAMPLE 15 Preparation of N-Hydroxy-N-(N-methyl-(3-phenoxyphenylbenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing N-methylethanolamine in lieu of ethanolamine toprovide a viscous oil. ¹ H NMR (300 MHz, DMSO-d₆); 9.23 (1H, s),7.38-7.48 (3H, m), 7.09-7.21 (2H, m), 6.90-7.07 (4H, m), 6.29 (2H, s),3.60 (3H, br s), 3.45 (1H, br s), 2.93 (1.5H, br s), 2.87 (1.5H, br s);MS (M+H)⁺ =330, (M+NH₄)⁺ =347 Analysis calc'd for C₁₇ H₁₉ N₃ O₄ (0.25 H₂O): C, 61.16 H, 5.89; N, 12.59; Found: C, 60.77; H, 5.88; N, 12.39.

EXAMPLE 16 Preparation of N-Hydroxy-N-2-((3-methoxybenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-methoxybenzoate in lieu of 3-phenoxybenzoate.m.p. 149°-150° C.: ¹ H NMR (300 MHz, DMSO-d₆); 9.33 (1H, s), 8.46 (1H,br t, J=4.5 Hz), 7.33-7.42 (3H, m), 7.07 (1H, dt, J=8, 2.5, 2.5 Hz),6.33 (2H, s), 3.71 (3H, s), 3.50 (2H, m), 3.45 (2H, m); MS (M+H)⁺ =254,(M+NH₄)⁺ =271; Analysis calc'd for C₁₁ H₁₅ N₃ O₄ : C, 52.17; H, 5.97; N,16.59; Found: C, 51.95; H, 5.87; N, 16.18.

EXAMPLE 17 Preparation of N-Hydroxy-N-2-((4-methoxybenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 4-methoxybenzoate in lieu of 3-phenoxybenzoate.m.p. 136°-138° C.: ¹ H NMR (300 MHz, DMSO-d₆); 9.33 (1H, s), 8.34 (1H,br t, J=4.5 Hz), 7.80 (2H, d, J=9.5), 6.98 (2H, d, J=9.5), 6.32 (2H, s),3.81 (3H, s), 3.48 (2H, m), 3.41 (2H, m); MS (M+H)⁺ =254, (M+NH₄)⁺ =271;Analysis calc'd for Analysis calc'd for C₁₁ H₁₅ N₃ O₄ : C, 52.17; H,5.97; N, 16.59; Found: C, 51.96; H, 5.98; N, 16.09.

EXAMPLE 18 Preparation of N-Hydroxy-N-2-((4-butoxybenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 4-butoxybenzoate in lieu of 3-phenoxybenzoate.m.p. 156°-157° C.: ¹ H NMR(300MHz, DMSO-d₆); 9.33(1H, s),8.32(1H, br t,J=4.5 Hz), 7.78 (2H, d, J=9.5), 6.98 (2H, d, J=9.5), 6.33 (2H, s), 4.03(2H, t, J=6 Hz), 3.48 (2H, m), 3.41 (2H, m), 1.71 (2H, pentet, J=8 Hz),1.45 (2H, sextet, J=8 Hz), 0.94 (3H, t, J=8 Hz); MS (M+H)⁺ =296;Analysis calc'd for C₁₄ H₂₁ N₃ O₄ : C, 56.94; H, 7.17; N, 13.84; Found:C, 56.59; H, 7.14; N, 13.84.

EXAMPLE 19 Preparation of N-Hydroxy-N-((3-butoxybenzoyl)amino)ethyl!urea

3-butoxybenzoate was prepared by adding ethyl 3-hydroxybenzoate (15 g,90.3 mmol) and N-butyliodide (20.5 mL, 180.5 mmol) in THF (300 mL) to anambient temperature THF (500 mL) solution of NaH (97%, 3.35 g, 135.4mmol) under an nitrogen atmosphere. To the resulting soution was addedhexamethylphosphoramide (HMPA, 31.5 mL, 180.5 mmol). The reaction washeated at relux for 1 h, cooled to ambient temperature and the volatilesremoves under vacuum. The resulting oil was dissolved in ethanol (300mL) and sodium hydroxide (3.6 g, 180.5 mmol) was added in water (100mL); the hydrolysis of the ester was complete after 1 h at ambienttemperature. The volatiles were removed under vacuum and the resultingslurry acidified to pH=2 with 10% aqueous HCl and extracted (2×, EtOAc).The combined organic extracts were washed (1×, brine), dried (Na₂ SO₄),filtered, and concentrated in vacuo to provide a light yellow solid. Thetitle compound was obtained following the procedures described inExample 2, but employing the 3-butoxybenzoate in lieu of3-phenoxybenzoate. m.p. 153.5°-154.5° C.: ¹ H NMR (300 MHz, DMSO-d₆);9.32 (1H, s), 8.43 (1H, br t, J=4.5 Hz), 7.33-7.42 (3H, m), 7.07 (1H,dt, J=8, 2.5, 2.5 Hz), 6.33 (2H, s), 4.01 (2H, t, J=6 Hz), 3.48 (2H, m),3.43 (2H, m), 1.71 (2H, br pentet, J=8 Hz), 1.45 (2H, br sextet, J=8Hz), 0.94 (3H, t, J=8 Hz); MS (M+H)⁺ =296, (M+NH₄)⁺ =313(weak); Analysiscalc'd for C₁₄ H₂₁ N₃ O₄ : C, 56.94; H, 7.17; N, 13.84; Found: C, 56.88;H, 7.17; N, 14.16.

EXAMPLE 20 Preparation of N-Hydroxy-N-2-((4-chlorobenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 4-chlorobenzoate in lieu of 3-phenoxybenzoate.m.p. 172°-173° C.: ¹ H NMR (300 MHz, DMSO-d₆); 9.33 (1H, s), 8.46 (1H,br t, J=4.5 Hz), 7.83 (2H, d, J=7.5), 7.53 (2H, d, J=7.5), 6.32 (2H,s),3.50 (2H, m), 3.43 (2H, m); MS (M+H)⁺ =254, (M+NH₄)⁺ =271; Analysiscalc'd for Analysis calc'd for C₁₀ H₁₂ N₃ O₃ Cl(0.20 H₂ O): C, 45.97; H,4.78; N, 16.08; Found: C, 45.99; H, 4.30; N, 16.03.

EXAMPLE 21 Preparation of N-Hydroxy-N-3-(((3-phenoxybenzoyl)amino)propyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-aminopropanol in lieu of 2-aminoethanol. m.p.135.5°-138° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.25 (1H, s), 8.50 (1H, t,J=5 Hz), 7.63 (1H, dt, J=8,1,1), 7.38-7.52 (4H, m), 7.18 (2H, m), 7.03(2H, dq, J=7,1,1,1, Hz), 6.30 (2H, s), 3.37 (2H, t, J=7.5), 3.25 (2H, q,J=7.5), 1.73 (2H, pentet, J=7.5); MS (M+H)⁺ =330, (M+NH₄)⁺ =347.Analysis calc'd for C₁₇ H₁₉ N₃ O₄ (0.25 H₂ O): C, 61.16; H, 5.89; N,12.59; Found: C, 61.07; H, 5.79; N, 12.74.

EXAMPLE 22 Preparation of N-Hydroxy-N-4-((3-phenoxybenzoyl)amino)butyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 4-aminobutanol in lieu of 2-aminoethanol. m.p.131°-133° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.20 (1H, s), 8.50 (1H, t, J=5Hz), 7.63 (1H, d, J=8), 7.38-7.52 (4H, m), 7.18 (2H, br t, J=7.5 Hz),7.03 (2H, br d, J=7.5 Hz), 6.32 (2H, s), 3.37 (2H, br m), 3.23 (2H, brq, J=6 Hz), 1.50 (4H,br m); MS (M+H)⁺ =344, (M+NH₄)⁺ =361 (weak).Analysis calc'd for C₁₈ H₂₁ N₃ O₄ (0.25 H₂ O): C, 62.96; H, 6.16; N,12.24; Found: C, 62.52; H, 6.16; N, 12.08.

EXAMPLE 23 Preparation of N-Hydroxy-N'-methyl-N-3-((3-phenoxybenzoyl)amino)propyl!urea

The title compound was obtained following the procedures described inExample 26, but employing N-methylisocyanate in lieu of N-trimethylsilylisocyanate. m.p. 175°-177° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.18 (1H, s),8.48 (1H, t, J=5 Hz), 7.63 (1H, d, J=8), 7.38-7.52 (4H, m), 7.18 (2H,m), 7.05 (2H, dq, J=7,1,1,1, Hz), 6.83 (1H, q, J=6 Hz), 3.34 (2H, t,J=7.5), 3.25 (2H, q, J=7.5), 2.58 (3H, d, J=6 Hz), 1.73 (2H, pentet,J=7.5); MS (M+H)⁺ =344. Analysis calc'd for C₁₈ H₂₁ N₃ O₄ : C, 62.96; H,6.16; N, 12.24; Found: C, 62.52; H, 6.14; N, 12.08.

EXAMPLE 24 Preparation of N-Hydroxy-N'-methyl-N-2-((3-phenoxybenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing N-methylisocyanate in lieu of N-trimethylsilylisocyanate. m.p. 161°-162.5° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.22 (1H,s), 8.48 (1H, t, J=5 Hz), 7.63 (1H, d, J=8), 7.38-7.52 (4H, m), 7.18(2H, m), 7.05 (2H, dq, J=7,1,1,1, Hz), 6.87 (1H, q, J=6 Hz), 3.37-3.52(4H, m), 2.58 (3H, d, J=6 Hz); MS (M+H)⁺ =330, (M+NH₄)⁺ =347. Analysiscalc'd for C₁₇ H₁₉ N₃ O₄ : C, 62.00; H, 5.81; N, 12.76; Found: C, 62.10;H, 5.86; N, 12.73.

EXAMPLE 25 Preparation of N-Hydroxy-N-2-((3-(3-trifluoromethylphenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-(3-trifluoromethylphenoxy)benzoate in lieu of3-phenoxybenzoate. m.p. 126°-128° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.28(1H, s), 8.52 (1H, t, J=5 Hz), 7.56-7.67 (2H, m), 7.52-7.47 (3H, m),7.19-7.33 (3H, m), 6.28 (2H, s), 3.47 (2H, m), 3.37 (2H, m), 1.73 (2H,pentet, J=7.5); MS (M+H)⁺ =384, (M+NH₄)⁺ =401. Analysis calc'd for C₁₇H₁₆ F₃ N₃ O₄ : C, 53.27; H, 4.21; N, 10.96; Found: C, 53.10; H, 4.28; N,10.87.

EXAMPLE 26 Preparation of N-Hydroxy-N-2-((3-(4-chlorophenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-(4-chlorophenoxy)benzoate in lieu of3-phenoxybenzoate. m.p. 146°-147° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31(1H, s), 8.53 (1H, t, J=5 Hz), 7.63 (1H, br d, J=7.5 Hz), 7.52-7.43 (4H,m), 7.21 (1H, dd, J=7.5, 3 Hz), 7.06 (2H, d, J=9.5 Hz), 6.33 (2H, s),3.48 (2H, m), 3.42 (2H, m); MS (M+H)⁺ =350, (M+NH₄)⁺ =367. Analysiscalc'd for C₁₆ H₁₆ ClN₃ O₄ : C, 54.94; H, 4.61; N, 12.01; Found: C,54.90; H, 4.58; N, 11.55.

EXAMPLE 27 Preparation of N-Hydroxy-N'-methyl-N-2-((3-(4-chlorophenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 26, but employing N-methylisocyanate in lieu of N-trimethylsilylisocyanate. m.p. 157°-158° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.24 (1H, s),8.53 (1H, t, J=5 Hz), 7.63 (1H, br d, J=7.5 Hz), 7.52-7.43 (4H, m), 7.21(1H, dd, J=7.5, 3 Hz), 7.06 (2H, d, J=9.5 Hz), 6.87 (1H, q, J=5 Hz),3.52-3.38 (4H, m), 2.56 (1H, d, J=5 Hz); MS (M+H)⁺ =364, (M+NH₄)⁺ =381.Analysis calc'd for C₁₇ H₁₈ ClN₃ O₄ (0.25 H₂ O): C, 55.44; H, 5.06; N,11.41; Found: C, 55.70; H, 5.06; N, 11.34.

EXAMPLE 28 Preparation of N-Hydroxy-N-2-((3-(4-methoxyphenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-(4-methoxyphenoxy)benzoate in lieu of3-phenoxybenzoate. m.p. 160°-162° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31(1H, s), 8.50 (1H, t, J=5 Hz), 7.53 (1H, br d, J=7.5 Hz), 7.42 (1H, t,J=7.5 Hz), 7.35 (1H, br s), 7.10-6.96 (5H, m), 6.33 (2H, s), 3.77 (3H,s), 3.48 (2H, m), 3.40 (2H, m); MS (M+H)⁺ =346. Analysis calc'd for C₁₇H₁₉ N₃ O₅ : C, 59.12; H, 5.55; N, 12.17; Found: C, 59.06; H, 5.52; N,11.98.

EXAMPLE 29 Preparation of N-Hydroxy-N-2-((3-(3,4-dichlorophenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-(3,4-dichlorophenoxy)benzoate in lieu of3-phenoxybenzoate. m.p. 153°-156° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.33(1H, s), 8.54 (1H, t, J=5 Hz), 7.68 (1H, br d, J=7 Hz), 7.65 (1H, d, J=9Hz), 7.53 (1H, d, J=9 Hz), 7.37 (1H, d, J=3), 7.27 (1H, dd, J=9,3 Hz),7.03 (1H, dd, J=9,3 Hz), 6.33 (2H, s), (3.77 (3H, s), 3.48 (2H, m), 3.42(2H, m); MS (M+H)⁺ =384. Analysis calc'd for C₁₆ H₁₅ Cl₂ N₃ O₄ : C,50.02; H, 3.93; N, 10.94; Found: C, 50.15; H, 4.02; N, 10.34.

EXAMPLE 30 Preparation of N-Hydroxy-N-2-((3-(3,5-dichlorophenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-(3,5-dichlorophenoxy)benzoate in lieu of3-phenoxybenzoate. m.p. 164°-166° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.33(1H, s), 8.56 (1H, t, J=5 Hz), 7.70 (1H, br d, J=7.5 Hz), 7.55 (1H,t,J=7.5 Hz), 7.53 (1H, br s), 7.40 (1H, t, J=1.5), 7.29 (1H, dd, J=7.5,3Hz), 7.10 (2H, d, J=1.5 Hz), 6.33 (2H, s), (3.77 (3H, s), 3.48 (2H, m),3.42 (2H, m); MS (M-CHNO)⁺ =341. Analysis calc'd for C₁₆ H₁₅ Cl₂ N₃ O₄ :C, 50.02; H, 3.93; N, 10.94; Found: C, 49.83; H, 3.83; N, 10.82.

EXAMPLE 31 Preparation of N-Hydroxy-N-2-((3-(4-tert-butylphenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-(4-t-butylphenoxy)benzoate in lieu of3-phenoxybenzoate. m.p. 100°-102° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31(1H, s), 8.53 (1H, t, J=5 Hz), 7.59 (1H, br d, J=7.5 Hz), 7.39-7.50 (4H,m), 7.15 (1H, dd, J=7.5, 3 Hz), 6.97 (2H, d, J=9.5 Hz), 6.33 (2H, s),3.48 (2H, m), 3.42 (2H, m), 1.29 (9H, s); MS (M+H)⁺ =372. Analysiscalc'd for C16H₁₆ ClN₃ O₄ : C, 54.94; H, 4.61; N, 12.01; Found: C,54.90; H, 4.58; N, 11.55.

EXAMPLE 32 Preparation of (R)-N-Hydroxy-N-2-((3-phenoxybenzoyl)amino)propyl!urea

The title compound was obtained following the procedures described inExample 2, but employing (R)-(-)-2-amino-1-propanol in lieu ofethanolamine. m.p. 153.5°-154° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31 (1H,s), 8.34 (1H, d, J=8 Hz), 7.61 (1H, br d, J=7.5 Hz), 7.38-7.50 (4H, m),7.17 (2H, br t, J=6.5), 7.03 (2H, br d, J=7.5 Hz), 6.30 (2H, s), 4.24(1H, septet, J=6.5Hz), 3.48 (1H, ABX, J=13,8 Hz), 3.42 (1H, ABX, J=13,7Hz), 1.13 (3H, d, J=6.5Hz); MS (M+H)⁺ =330, (M+NH₄)⁺ =347. Analysiscalc'd for C₁₇ H₁₉ N₃ O_(H) (0.25 H₂ O): C, 61.16; H, 5.89; N, 12.59;Found: C, 61.42; H, 5.81; N, 12.56.

EXAMPLE 33 Preparation of (d,l)-N-Hydroxy-N-3-((3-phenoxybenzoyl)amino)prop-2-yl!urea

The title compound was obtained following the procedures described inExample 2, but employing 1-amino-2-propanol in lieu of ethanolamine.m.p. 189°-190° C.; ¹ H NMR (300 MHz, DMSO-d₆); 8.80 (1H, s), 8.48 (1H,t, J=5 Hz), 7.59 (1H, br d, J=8 Hz), 7.48 (1H, t, J=8 Hz), 7.38-7.45(3H, m), 7.14-7.22 (2H, m), 7.04 (2H, br d, J=7.5 Hz), 6.30 (2H, s),4.27 (1H, sextet, J=6.5Hz), 3.18-3.38 (2H,m), 0.98 (3H, d, J=6.5Hz); MS(M+H)⁺ =329, (M+NH₄)⁺ =347. Analysis calc'd for C₁₇ H₁₉ N₃ O₄ : C,62.00; H, 5.81; N, 12.76; Found: C, 61.78; H, 5.85; N, 12.73.

EXAMPLE 34 Preparation of N-Hydroxy-N-2-((4-phenylbenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 4-phenylbenzoate in lieu of 3-phenoxybenzoate.m.p. 160°-162° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.36 (1H, s), 8.53 (1H,t, J=5 Hz), 7.92 (2H, d, J=9 Hz), 7.72-7.8 (4H, m), 7.49 (2H, br t,J=7.5 Hz), 7.40 (1H, t, J=7.5 Hz), 6.35 (2H, s), 3.42-3.57 (4H, m); MS(M+H)⁺ =300, (M+NH₄)⁺ =317. Analysis calc'd for C₁₆ H₁₇ N₃ O₃ (0.10 H₂O): C, 63.82; H, 5.76; N, 13.95; Found: C, 64.26; H, 5.76; N, 13.52.

EXAMPLE 35 Preparation of N-Hydroxy-N-2-((3-phenylmethyloxybenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-benzyloxybenzoate in lieu of3-phenoxybenzoate. m.p. 183°-185° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.33(1H, s), 8.46 (1H, t, J=5 Hz), 7.30-7.50 (8H, m), 7.17 (1H, br d, J=8Hz), 6.33 (2H, s), 5.14 (2H, s), 3.38-3.54 (4H, m); MS (M+H)⁺ =330,(M+NH₄)⁺ =347. Analysis calc'd for C₁₇ H₁₉ N₃ O₄ : C, 62.00; H, 5.81; N,12.76; Found: C, 62.40; H, 6.37; N, 11.49.

EXAMPLE 36 Preparation of N-Hydroxy-N-2-((5-phenoxyfuran-2-oyl)amino)ethyl!urea

Step 1: Preparation of 5-phenoxy-2-furoic acid

A flask was charged with 5-nitro-2-furoic acid (15.02 g, 95.62 mmol),absolute ethanol (100 mL), and concentrated sulfuric acid (1 mL) andrefluxed overnight. After cooling the reaction mixture, the volatileswere removed under vacuum, the resulting slurry taken up into ethylacetate, and washed sequentially (1×, NaHCO₃ ; 1×, brine), dried(MgSO₄), filtered and concentrated under vacuum to provide thecorresponding ester as a light yellow solid (15.31 g, 87%) which wasused without further purification.

A flask was charged with NaH (2.9 g, 96.7 mmol, 80% suspension in oil),and dimethylsulfoxide (DMSO)(200 mL), and flushed with nitrogen. To thissolution was added neat phenol (9.1 g, 96.7 mmol) in a portionwisefashion; the reaction was stirred under nitrogen until gas evolutionceased. A solution of 5-nitro-2-furoic acid (14.92 g, 80.6 mmol) in DMSO(120 mL) was then added to the reaction to give a dark purple solutionwhich was judged to be complete by thin layer chromatography after 0.5h. The reaction was poured into saturated aqueous NaHCO₃ and extractedwith ethyl acetate (3×). The combined organic extracts were washed (3×,H₂ O), dried (MgSO₄), filtered and concentrated under vacuum to providethe corresponding phenoxy ester as an orange-brown liquid (21.11 g,113%) contaminated with phenol which was used without furtherpurification.

The unpurified phenoxy ester (5 g, 18.3 mmol) was dissolved in dioxaneand water added until the reaction permanently clouded. Under a constantnitrogen flow, LiOH(H₂ O) (1.23 g, 29.26 mmol) was added. The resultingmixture was stirred at ambient temperature for 2 h, and poured intowater. The resulting solution was extracted with ether and the organiclayer drawn off. The aqueous layer was acidified to pH˜1 and extractedwith ethyl acetate (2×). The combined organic extracts were washed (3×,H₂ O), dried (MgSO₄), filtered and concentrated under vacuum to providethe corresponding phenoxy acid as a white solid. Recrystallization fromether/hexanes provided the pure title compound (3.05 g, 82%). m.p.131°-132° C.; ¹ H NMR (300 MHz, D₆ -DMSO); 10.20 (1H, br s), 7.39 (2H,t, J=8 Hz), 7.31 (1H, d, J=3 Hz), 7.23 (1H, t, J=8 Hz), 7.14 (2H, t, J=8Hz), 5.53 (1H, d, J=3 Hz); MS (M+H)⁺ =205, (M+NH₄)⁺ =222.

Step 2: Preparation of N-Hydroxy-N-2-((5-phenoxyfuran-2-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 5-phenoxy-2-furanoic acid (prepared in step 1,above) in lieu of 3-phenoxybenzoate. m.p. 160°-163° C.; ¹ H NMR (300MHz, DMSO-D₆); 9.28 (1H, s), 8.22 (1H, t, J=5 Hz), 7.45 (2H, t, J=8 Hz),7.23 (1H, t, J=8 Hz), 7.16 (1H, d, J=8 Hz), 7.10 (2H, d, J=3 Hz), 6.33(2H, s), 5.86 (1H, d, J=3 Hz) 3.30-3.49 (4H, m); MS (M+H)⁺ =306,(M+NH₄)⁺ =323. Analysis calc'd for C₁₄ H₁₅ N₃ O₅ (0.10 H₂ O): C, 54.76;H, 4.99; N, 13.68; Found: C, 54.57; H, 4.94; N, 13.33.

EXAMPLE 37 Preparation of N-Hydroxy-N-2-(N-methyl-((3-(4-chlorophenoxy)phenyl)methyl)amino)ethyl!urea

Step 1: Preparation ofN-Methyl-N-(3-(4-chlorophenoxy)phenylmethyl)-2-aminoethanol

A flask was charged with N-methyl ethanolamine (4.88 mL, 60.68 mmol),hydrochloric acid (4.5 mL of 4.5M HCl in dioxane, 20.23 mmol), andabsolute ethanol (20 mL). To the resulting solution was added3-(4-chlorophenoxy)phenylcarboxaldehyde (4.0 mL, 20.23 mmol) in ethanol(20 mL) and in small portions NaCNBH₃ (1.27 g, 20.23 mmol). The reactionwas stirred at ambient temperature for 1.5 h and the volatiles removedunder vacuum. The residue was carefully dissolved in excess 10% aqueousHCl, the pH adjusted to greater than pH 10 with freshly prepared 15%aqueous NaOH, and the resulting suspension was extracted with ethylacetate (2×). The combined organic extracts were washed (2×, brine),dried (MgSO₄), filtered and concentrated under vacuum to provide theunpurified aminoalcohol. Chromatographic purification (silica gel, 500mL 20% ethyl acetate/ hexanes, 500 mL ethyl acetate, 1 L 10%methanol/ethyl acetate) provided the corresponding aminoalcohol as aviscous oil (2.99 g, 51%). m.p. 131°-132° C.; ¹ H NMR (300 MHz, D₆-DMSO) 7.25-7.32 (3H, m), 6.85-6.97 (4H, m), 3.62 (2H, t, J=6 Hz), 3.53(2H, s), 2.58 (2H, t, J=6 Hz), 2.52 (1H, br s), 2.23 (3H, s); MS (M+H)⁺=292.

Step 2: Preparation of N-Hydroxy-N-2-(N-methyl-((3-(4-chlorophenoxy)phenyl)methyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing the amino ethanol (prepared as described instep 1, above) in lieu of the amide alcohol. m.p. 111°-113° C.; ¹ H NMR(300 MHz, DMSO-D₆); 9.23 (1H, s), 7.43 (2H, d, J=9 Hz), 7.33 (1H, t, J=8Hz), 7.10 (1H, d, J=8 Hz), 7.02 (2H, d, J=9 Hz), 6.98 (1H, br s), 6.90(1H, dd, J=8,3 Hz), 6.23 (2H, s), 3.49 (2H,s), 2.50 (2H, t, J=7.5 Hz),2.13 (3H, s); MS (M+H)⁺ =350. Analysis calc'd for C₁₇ H₂₀ N₃ O₃ Cl: C,58.37; H, 5.76; N, 12.01; Found: C, 58.12; H, 5.75; N, 11.88.

EXAMPLE 38 Preparation of N-Hydroxy-N-2-(N-methyl-((3-(4-methoxyphenoxy)phenyl)ethyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employingN-methyl-N-(3-(4-methoxyphenoxy)phenylmethyl)-2-aminoethanol (preparedas in Example 37, step 1 from 3-(4-methoxyphenoxy)phenylcarboxaldehyde)in lieu of 3-(4-chlorophenoxy)phenylcarboxaldehyde. m.p. 87°-88.5° C.; ¹H NMR (300 MHz, DMSO-d₆); 9.23 (1H, s), 7.27 (1H, t, J=8 Hz), 6.92-7.02(5H, m),6.88 (1H, br s), 6.78 (1H, dd, J=8,3 Hz), 6.23 (2H, s), 3.76(3H, s), 3.41-3.48 (4H, m), 2.47-2.52 (2H, m), 2.13 (3H, s); MS (M+H)⁺=346. Analysis calc'd for C₁₈ H₂₃ N₃ O₄ : C, 62.59; H, 6.71; N, 12.17;Found: C, 62.39; H, 6.76; N, 12.13.

EXAMPLE 39 Preparation of N-Hydroxy-N-2-(N-methyl((3-(3,4-dichlorophenoxy)phenyl)methyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employingN-methyl-N-(3-(3,4-methoxyphenoxy)phenylmethyl)-2-aminoethanol (preparedas in Example 37, step 1 from3-(3,4-dichlorophenoxy)phenylcarboxaldehyde) in lieu of3-(4-chlorophenoxy)phenylcarboxaldehyde. m.p. 107°-109° C.; ¹ H NMR (300MHz, DMSO-d₆); 9.23 (1H, s), 7.63 (1H,d, J=9 Hz), 7.37 (1H, t, J=8 Hz),7.29 (1H, d, J=3 Hz), 7.16 (1H. br d, J=8 Hz), 7.03 (1H, br s),6.94-7.00 (2H, m), 6.23 (2H, s), 3.50 (2H, s), 3.45 (2H, t, J=6.5 Hz),2.50 (2H, t, J=6.5 Hz), 2.13 (3H, s); MS (M+H)⁺ =384/386. Analysiscalc'd for C₁₇ H₁₉ N₃ O₃ Cl₂ : C, 53.14; H, 4.98; N, 10.94; Found: C,52.93; H, 4.94; N, 10.79.

EXAMPLE 40 Preparation of N-Hydroxy-N-2-(N-methyl-((3-(3,5-dichlorophenoxy)phenyl)methyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employingN-methyl-N-(3-(3,5-methoxyphenoxy)phenylmethyl)-2-aminoethanol (preparedas in step 1, example 37 from3-(3,5-dichlorophenoxy)phenyl)carboxaldehyde) in lieu of theamidealcohol: m.p. 111°-113° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.23 (1H,s), 7.33-7.42 (2H, m), 7.29 (1H, d, J=7.5 Hz), 6.96-7.08 (3H, m), 6.23(2H, s), 3.50 (2H, s), 3.47 (2H, t, J=6.5 Hz), 2.52 (2H, t, J=6.5 Hz),2.13 (3H, s); MS (M+H)⁺ =384/386. Analysis calc'd for C₁₇ H₁₉ N₃ O₃ Cl₂: C, 53.14; H, 4.98; N, 10.94; Found: C, 53.02; H, 4.88; N, 10.75.

EXAMPLE 41 Preparation of N-Hydroxy-N-2-(((((4-methoxy-3-phenylmethoxy)phenyl)methyl)N-methyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employingN-methyl-N-(3-(benzyloxy)-4-methoxyphenylmethyl)-2-aminoethanol(prepared as in step 1, example 37 from3-(benzyloxy)-4-methoxyphenylcarboxaldehyde) in lieu of3-(4-chlorophenoxy)phenylcarboxaldehyde m.p. 108°-111° C.; ¹ H NMR (300MHz, DMSO-d₆); 9.27 (1H, s), 7.30-7.48 (5H, m), 7.01 (1H, br s), 6.90(1H, d, J=8, Hz), 6.81 (1H, br d, J=8, Hz), 6.27 (2H, s), 5.05 (2H, s),3.76 (3H, s), 3.49 (2H, t, J=7.5 Hz), 3.42 (2H, br s), 2.47-2.52 (2H,m), 2.12 (3H, s); MS (M+H)⁺ =360. Analysis calc'd for C₁₉ H₂₅ N₃ O₄ : C,63.49; H, 7.01; N, 11.69; Found: C, 63.05; H, 7.05; N, 11.56.

EXAMPLE 42 Preparation of (S)-N-Hydroxy-N-2-((tert-butoxycarbonyl)amino)propyl!urea

(S)-N-Boc-alaninol (13.5 g, 77 mmol) and triethylamine (43 mL, 308 mmol)were dissolved in dichloromethane (45 mL) and cooled to 0° C. A solutionof sulfur trioxide pyridine (36.8 g, 231.1 mmol) in DMSO (45 mL, gentlewarming is needed to achieve complete dissolution) was added rapidly tothe reaction solution. The cooling bath was removed 15 minutes afteraddition was completed and the reaction monitored for completion by tlcanalysis of quenched aliquots. The reaction was judged to be completeafter 30 minutes, poured into brine, and extracted with ethyl acetate(2×). The combined organic layers were washed with 10% aqueous HCl (2×),brine (2×), dried (MgSO₄), filtered, and concentrated in vacuo to givean oil which solidified upon vacuum drying to give the correspondingaldehyde (12.95 g, 96%). The aldehydes are not stable and are bestimmediately convened to the oxime.!

The aldehyde is dissolved in ethanol (300 mL) and hydroxylaminehydrochloride (10.7 g, 110.5 mmol) and pyridine (6.2 mL, 77 mmol) wereadded. The reaction was stirred at ambient temperature until judgedcomplete (typically 1-2 hours) by thin layer chromatography. Thevolatiles were removed in vacuo and the resulting slurry was partitionedbetween ethyl acetate and 10% aqueous HCl. The aqueous layer wasextracted (2×, ethyl acetate) and the combined organic layers washed(2×, saturated aqueous sodium bicarbonate; 2×, brine), dried (MgSO₄),filtered, and concentrated in vacuo to give the oxime as an oily solid(12.96 g, 89% which was carried on without further purification.

The oxime (6.0 g, 31.8 mmol) was dissolved in glacial acetic acid (110mL) and tetrahydrofuran (25 mL). The sodium cyanoborohydride (2.6 g,41.4 mmol) was added in a single portion. When gas evolution ceases andall of the sodium cyanoborohydride was dissolved the reaction wascomplete. The reaction was neutralized with 6N NaOH to pH˜7 and thensaturated aqueous sodium bicarbonate was added to adjust the pH to 9.The resulting two phased solution was extracted with ethyl acetate (3×).The combined organic layers were washed with brine (2×), dried (MgSO₄),filtered, and concentrated in vacuo to give the N-hydroxylamine as anoil (6.2 g, 100%). The unpurified N-hydroxylamine was best converted assoon as possible to the N-hydroxy urea to avoid decomposition.

The N-hydroxylamine (6.2 gm, 31.8 mmol) was dissolved in freshly driedtetrahydrofuran (100 mL) and treated with TMS-isocyanate (5 mL, 38.2mmol) at ambient temperature. The reaction was typically complete within1 hour, treated with water (1.15 mL, 64 mmol) and methanol (100 mL), andconcentrated in vacuo to provide the unpurified title compound as asolid (7.11 g). Recrystallization from ethyl acetate/methanol provided2.53 g (34%) of pure product. The mother liquors were chromatographed(200 g silica gel; column packed in dichloromethane and eluted with 5%methanol/dichloromethane) to provide 1.09 g (15%) of additional product.m.p. 156°-160° C.; ¹ H NMR (300 MHz, DMSO-D₆); 9.23 (1H, s), 6.64 (1H,br d J=8.0 Hz), 6.27 (2H, s), 3.72 (1H, septet, J=6.5 Hz), 3.35 (1H,ABX, J=13.0,8.0 Hz), 3.22 (1H, ABX, J=13.0,5.5 Hz), 1.38 (9H, s); MS(M+H)⁺ =234; (M+NH₄)⁺ =251. Analysis calc'd for C₉ H₁₉ N₃ O₄ (0.25 H₂O): C, 45.46; H, 8.27; N, 17.67; Found: C, 45.59; H, 7.83; N, 17.24.

EXAMPLE 43 Preparation of (R)-N-Hydroxy-N-2-((tert-butoxycarbonyl)amino)propyl!urea

The title compound was prepared according to the procedures describedfor the preparation of the (S)-isomer in example 42 by employing(R)-N-Boc-alaninol in lieu of (S)-N-Boc-alaninol. m.p. 156°-160° C.; ¹ HNMR (300 MHz, DMSO-D₆); 9.23 (1H, s), 6.64 (1H, br d J=8.0 Hz), 6.27(2H, s), 3.72 (1H, septet, J=6.5 Hz), 3.35 (1H, ABX, J=13.0,8.0 Hz),3.22 (1H, ABX, J=13.0,5.5 Hz), 1.38 (9H, s); MS (M+H)⁺ =234; (M+NH₄)⁺=251. Analysis calc'd for C₉ H₁₉ N₃ O₄ (0.25 H₂ O): C, 45.46; H, 8.27;N, 17.67; Found: C, 45.59; H, 7.83; N, 17.24.

EXAMPLE 44 Preparation of N-Hydroxy-N-2-((tert-butoxycarbonyl)amino)ethyl!urea

The title compound was prepared according to the procedures describedfor the preparation of the (S)-isomer in example 42 by employingN-Boc-ethanolamine in lieu of (S)-N-Boc-alaninol. m.p. 144°-145.5° C.; ¹H NMR (300 MHz, DMSO-D₆); 9.18 (1H, s), 6.62 (1H, br t, J=5.5 Hz), 6.27(2H, s), ca. 3.30 (2H, br t, J=6.5 Hz), 3.03 (2H, br q, J=6.5 Hz), 1.34(9H, s); MS (M+H)⁺ =220. Analysis calc'd for C₈ H₁₇ N₃ O₄ : C, 43.83; H,7.82; N, 19.17; Found: C, 44.09; H, 7.84; N, 19.38.

EXAMPLE 45 Preparation of N-Hydroxy-N-(((3-(4-chlorophenoxy)phenyl)prop-2-enyl)amino)carbonyl)methyl!urea

The title compound was obtained following the procedures described inExample 1, but employingtrans-1-amino-3-((4-chlorophenoxy)phenyl)-prop-2-ene (prepared accordingto the method of Dellaria (Dellaria, J. F.; Sallin, K. J. TetrahedronLett. 1990, 31, 2661)) in lieu of 4-phenoxyaniline. m.p. 150°-151° C.; ¹H NMR (300 MHz, DMSO-d₆); 9.40 (1H, s), 7.74 (1H, d, J=7.5 Hz),7.30-7.42 (3H, m), 7.10-7.22 (2H, m), 6.97-7.07 (3H, m), 6.88 (1H, dd,J=8, 2 Hz), 6.47 (1H, d, J=15.5 Hz), 6.43 (2H, s), 6.27 (1H, dd, J=15.5,6 Hz),4.53 (1H, sextet, J=6.5 Hz) 3.97(2H, s), 1.24 (3H, d, J=6.5 Hz);MS (M+H)⁺ =356, (M+NH₄)⁺ =373. Analysis calc'd for C₁₉ H₂₁ N₃ O₄ : C,64.21; H, 5.96; N, 11.82; Found: C, 64.29; H, 6.04; N, 11.80.

EXAMPLE 46 Preparation of N-Hydroxy-N-2-((3-(1-methylethoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-(1-methylethoxy)benzoate in lieu of3-phenoxybenzoate. The 3-(1-methylethoxy)benzoate was prepared asdescribed in Example 19 using isopropyl iodide in lieu of n-butyliodide. m.p. 174°-175° C.: ¹ H NMR (300 MHz, DMSO-d₆); 9.33 (1H, s),8.43 (1H, br t, J=6.0 Hz), 7.30-7.39 (3H, m), 7.15 (1H, dt,J=7.0,3.0,3.0), 6.33 (2H, s), 4.66 (1H, septet, J=6.0 Hz), 3.48 (2H, m),3.43 (2H, m), 1.28 (3H, d, J=5.5 Hz); MS (M+H)⁺ =282, (M+NH₄)⁺ =299;Analysis calc'd for C₁₃ H₁₉ N₃ O₄ : C, 55,50; H, 6.81; N, 14.94 Found:C, 55.39; H, 6.84 N, 14.86.

EXAMPLE 47 Preparation of N-Hydroxy-N-2-((3-(2-methyl-prop-2-enyloxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 3-(2-methylprop-2-enyloxy)benzoate in lieu of3-phenoxybenzoate. The 3-(2-methylprop-2-enyloxy)benzoate was preparedas described in Example 19 using isobutenyl bromide in lieu of n-butyliodide. m.p. 148°-149° C.: ¹ H NMR (300 MHz, DMSO-d₆); 9.29 (1H, s),8.46 (1H, br t, J=5.5 Hz), 7.34-7.43 (3H, m), 7.12 (1H, dt,J=8.5,2.0,2.0), 6.33 (2H, s), 5.08 (1H, br s), 4.97 (1H, br s),4.52 (2H,br s), 3.50 (2H, m), 3.44 (2H, m), 1.79 (3H, s); MS (M+H)⁺ =294,(M+NH₄)⁺ =311; Analysis calc'd for C₁₄ H₁₉ N₃ O₄ : C, 57.33; H, 6.53; N,14.33 Found: C, 57.34; H, 6.54 N, 14.27.

EXAMPLE 48 Preparation of N-Hydroxy-N-2-((naphth-2-ylsulfonyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 2-napthylsulfonyl chloride in lieu of3-phenoxybenzoyl chloride. m.p. 174° C. with decomposition: ¹ H NMR (300MHz, DMSO-d₆); 9.33 (1H, s), 8.44 (1H, br s), 8.13-8.2 (2H, m), 8.06(1H, br d, J=8.0 Hz), 7.83 (1H, dd, J=9,2 Hz), 7.63-7.78 (3H, m), 6.31(2H, s), 3.37 (2H, m), 2.92 (2H, br t, J=7.5 Hz); MS (M+H)⁺ =310,(M+NH₄)⁺ =327; Analysis calc'd for C₁₃ H₁₅ N₃ O₄ S: C, 50.48; H, 4.89;N, 13.58 Found: C, 50.37; H, 4.90 N, 13.05.

EXAMPLE 49 Preparation of N-Hydroxy-N- 2-(((1-(4-chlorophenylmethyl)pyrrol-2-yl)carbonyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing N-(4-chlorophenylmethyl)-2-carboxypyrrole(prepared in standard fashion from 2-carboxypyrrole) in lieu of3-phenoxybenzoyl chloride. m.p. 158°-160° C.; ¹ H NMR (300 MHz,DMSO-d₆); 9.31 (1H, s), 8.03 (1H, t, J=6.0 Hz), 7.36 (2H, d, J=9.0 Hz),7.13 (2H, d, J=9.0 Hz), 7.06 (1H, t, J=2 Hz), 6.78 (1H, dd, J=4.0,2.0Hz), 6.33 (2H, s), 6.08 (1H, dd, J=4.0,3.0 Hz), 5.56 (2H, s), 3.43 (2H,m), 3.33 (2H, m); MS (M+H)⁺ =337, (M+NH₄)⁺ =354. Analysis calc'd for C₁₅H₁₇ N₄ O₃ Cl: C, 53.50; H, 5.09; N, 16.64; Found: C, 53.44; H, 5.07; N,16.61.

EXAMPLE 50 Preparation of N-Hydroxy-N-2-(((3-(4-chlorophenoxy)benzoyl)-N-methyl)amino)propyl!urea

The title compound was obtained following the procedures described inExample 2, but employing d,l-N-methyl-alaninol in lieu of ethanol amine.¹ H NMR (300 MHz, DMSO-d₆, an ˜2:1 mixture of rotational isomers); 9.14and 9.12 (1H, s), 7.47 (2H, d, J=9.0 Hz), 7.38-7.49 (1H, m), 6.95-7.2(3H, m), 7.07 (2H, d, J=9.0 Hz), 6.27 and 6.22 (2H, s), 4.83 and 3.96(1H, br q, J=6.5 Hz), 3.52 and 3.70 (1H, br dd, J=13.5,8.5 Hz), 3.29(2H, m), 1.05 and 1.13 (3H, br d, J=6.5 Hz); MS (M+H)⁺ =378, (M+NH₄)⁺=395. Analysis calc'd for C18H₂₀ ClN₃ O_(l) (0-5 H₂ O): C, 55.89; H,5.47; N, 10.86; Found: C, 556.23; H, 5.59; N, 10.36.

EXAMPLE 51 Preparation of N-Hydroxy-N-2-((2-phenoxybenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inScheme III. To an ice-cooled solution of 2-phenoxybenzoate (5 g, 23.3mmol) in dichloromethane (80 mL) was added oxalyl chloride (5.92 g, 46.7mmol) in dichloromethane (15 mL) in a dropwise fashion over 10 minutes.After addition was complete the cooling bath was removed and thereaction was stirred until no further bubbling was observed (0.5-1.0 h).The volatiles were removed under vacuum and the resulting liquid wasdissolved in dichloromethane (90 mL) and concentrated under vacuum (2cycles) to insure complete removal of excess oxalyl chloride. To asolution of 2-phenoxybenzoyl chloride (245 rag, 1.05 mmol) in CH₂ Cl₂ (5mL) was added the hydroxyurea, (prepared as described in example 44)(231 mg, 1.05 mmol) followed by the dropwise addition of triethylamine(117 mg, 1.16 mmol) and a crystal of 4-dimethylaminopyridine. Thereaction was then stirred for 0.5 h and concentrated. The resultingresidue was taken up in trifluoroacetic acid (2 mL) and stirred for 0.50h. This solution was then concentrated and the resulting residue wasdissolved in CH₂ Cl₂ (5 mL); to this solution was added triethylamine(0.293 mL, 2.10 mmol) and aqueous saturated NaHCO₃ (10 mL). Afterstirring for 0.5 h the aqueous phase was drawn off and extracted (2×,EtOAc). The combined organic extracts were washed sequentially (1×,saturated NaHCO₃ ; 1×, brine), dried (MgSO₄), filtered and concentratedin vacuo to provide the title compound as a powdery solid which wasrecrystallized (EtOAc/MeOH) to yield analytically pure title compound(235 mg, 68%). m.p. 182.5°-185° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.33(1H, s), 8.24 (1H, br t, J=5 Hz), 7.72 (1H, dd, J=8,2 Hz), 7.36-7.49(3H, m), 7.21 (1H, dt, J=2,8,8 Hz), 7.16 (1H, tt, J=1,1,8,8 Hz), 7.03(1H, dq, J=8,1,1,1, Hz), 6.88 (1H, dd, J=8,1 Hz), 6.32 (2H, br s),3.31-3.45 (4H, m); MS (M+H)⁺ =316. Analysis calc'd for C₁₆ H₁₇ N₃ O₄ :C, 60.95; H, 5.43; N, 13.33; Found: C, 61.28; H, 5.51; N, 13.34.

EXAMPLE 52 Preparation of N-Hydroxy-N-2-((4-phenoxybenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 4-phenoxybenzoate in lieu of2-phenoxybenzoate. m.p. 185°-186° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.33(1H, s), 8.43 (1H, br t, J=5.5 Hz), 7.75 (2H, d, J=9 Hz), 7.43 (2H, dd,J=9,8 Hz), 7.21 (1H, t, J=8 Hz), 7.08 (1H, dq, J=8,1,1,1 Hz), 7.03 (2H,d, J=8 Hz), 6.32 (2H, br s), 3.39-3.53 (4H, m); MS (M+H)⁺ =316. Analysiscalc'd for C₁₆ H₁₇ N₃ O₄ : C, 60.95; H, 5.43; N, 13.33; Found: C, 60.49;H, 5.46; N, 13.17.

EXAMPLE 53 Preparation of N-Hydroxy-N-2-(3-((4-bromophenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 3-(4-bromophenoxy)benzoate in lieu of2-phenoxybenzoate. m.p. 186°-187° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.33(1H, s), 8.46 (1H, br t, J=5.5 Hz), 7.87 (2H, d, J=9 Hz), 7.60 (2H, d,J=9 Hz), 7.07 (2H, d, J=9 Hz), 7.04 (2H, d, J=9 Hz), 6.32 (2H, br s),3.39-3.53 (4H, m); MS (M+H)⁺ =394/396; (M+NH₄)⁺ =411/413. Analysiscalc'd for C₁₆ H₁₆ N₃ O₄ Br(0.5 H₂ O): C, 47.66; H, 4.25; N, 10.42;Found: C, 47.76; H, 4.02; N, 10.28.

EXAMPLE 54 Preparation of N-Hydroxy-N-2-(3-((4-fluorophenoxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 3-(4-fluorophenoxy)benzoate in lieu of2-phenoxybenzoate. m.p. 179°-181° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31(1H, s), 8.52 (1 H, br t, J=5.5 Hz), 7.59 (1H, br d, J=8 Hz), 7.47 (1H,t, J=8 Hz), 7.42 (1H, dd, J=2,1 Hz), 7.26 (2H, t, J=9 Hz), 7.08-7.15(1H, m), 7.10 (2H, dd, J=9,4.5 Hz), 6.32 (2H, br s), 3.39-3.53 (4H, m);MS (M+H)⁺ =334; (M+NH₄)⁺ =351. Analysis calc'd for C₁₆ H₁₆ N₃ O₄ F: C,57.66; H, 4.84; N, 12.61; Found: C, 57.39; H, 4.79; N, 12.45.

EXAMPLE 55 Preparation of N-Hydroxy-N-2-((3-(pyrid-2-yloxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 3-(2-pyridinyloxy)benzoate in lieu of2-phenoxybenzoate. m.p. 159°-160° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31(1H, s), 8.53 (1H, br t, J=5.5 Hz), 8.17 (1H, dd, J=4.5,2 Hz), 7.88 (1H,ddd, J=8.5,6.5,2 Hz), 7.68 (1H, br d, J=8.5 Hz), 7.56 (1H, t, J=2 Hz),7.50 (1H, t, J=8.5 Hz), 7.29 (1H, dd, J=8,2 Hz), 7.16 (1H, dd, J=7,4Hz), 7.08 (1H, d, J=8 Hz), 6.32 (2H, br s), 3.39-3.53 (4H, m); MS (M+H)⁺=317. Analysis calc'd for C₁₅ H₁₆ N₄ O₄ : C, 56.96; H, 5.10; N, 17.71;Found: C, 56.61; H, 5.06; N, 17.32.

EXAMPLE 56 Preparation of N-Hydroxy-N-2-((3-phenoxyphenylacetyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing (3-phenoxyphenyl)acetate in lieu of2-phenoxybenzoate. m.p. 150°-152° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.27(1H, s), 8.03 (1H, br t, J=5.5 Hz), 7.39 (2H, t, J=8 Hz), 7.30 (1H, t,J=8 Hz), 7.14 (1H, tt, J=7.5,0.5 Hz), 6.98-7.03 (3H,m), 6.92 (1H, t, J=2Hz), 6.85 (1H, br d, J=8 Hz), 6.32 (2H, br s), 3.39 (2H, s), 3.30-3.38(2H, m), 3.17-3.25 (2H, m), MS (M+H)⁺ =330; (M+NH₄)⁺ =347. Analysiscalc'd for C₁₇ H₁₉ N₃ O₄ : C, 62.00; H, 5.80; N, 12.76; Found: C, 61.74;H, 5.80; N, 12.66.

EXAMPLE 57 Preparation of N-Hydroxy-N-2-((4-n-hexyloxybenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 4-hexyloxybenzoate in lieu of2-phenoxybenzoate. m.p. 148°-151° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.34(1H, s), 8.33 (1H, br t, J=5.5 Hz), 7.78 (2H, d, J=8.5 Hz), 6.97 (2H, d,J=8.5 Hz), 6.32 (2H, br s), 4.00 (2H, t, J=6.5 Hz), 3.37-3.52 (4H, m),1.72 (2H, pentet, J=6.5 Hz), 1.25-1.48 (6H, m), 0.87 (3H, br t, J=6.5Hz); MS (M+H)⁺ =324. Analysis calc'd for C₁₆ H₂₅ N₃ O₄ : C, 59.43; H,7.79; N, 12.99; Found: C, 59.28; H, 7.74; N, 12.53.

EXAMPLE 58 Preparation of N-Hydroxy-N-2-((5-(4-chlorophenoxy)furan-2-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 5-(4-chlorophenoxy)-2-furanoic acid (preparedas in example 36, step 1 by using 4-chlorophenol in lieu of phenol) inlieu of 3-phenoxybenzoate. 64: m.p. 173°-175° C.; ¹ H NMR (300 MHz,DMSO-d₆); 9.28 (1H, s), 8.23 (1H, t, J=5 Hz), 7.50 (2H, d, J=9 Hz), 7.21(2H, d, J=9 Hz), 7.12 (1H, d, J=3 Hz), 7.10 (2H, d, J=3 Hz), 6.36 (2H,s), 5.92 (1H, d, J=3 Hz), 3.30-3.49 (4H, m); MS (M+H)⁺ =340/342.Analysis calc'd for C₁₄ H₁₄ N₃ O₅ Cl: C, 49.50; H, 4.15; N, 12.37;Found: C, 50.48; H, 4.29; N, 12.33.

EXAMPLE 59 Preparation of N-Hydroxy-N-2-((4-(4-chlorothiophenoxy)thien-3-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 4-(4-chlorothiophenoxy)-3-thiophenecarboxylicacid in lieu of 3-phenoxybenzoate. m.p. 157°-158° C.; ¹ H NMR (300 MHz,DMSO-d₆); 9.33 (1H, s), 8.23 (1H, t, J=5 Hz), 8.12 (1H, d, J=3 Hz), 7.46(2H, AB, J=9 Hz), 7.39 (2H, AB, J=9 Hz), 7.01 (1H, d, J=3 Hz), 6.36 (2H,s), 3.30-3.49 (4H, m); MS (M+H)⁺ =340/342. Analysis calc'd for C₁₄ H₁₄N₃ O₃ ClS₂ : C, 45.22; H, 3.79; N, 11.30; Found: C, 45.23; H, 3.80; N,11.01.

EXAMPLE 60 Preparation of (S)-N-Hydroxy-N-2-((5-(4-fluorophenoxy)fur-2-oyl)amino)propyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 5-(4-fluorophenoxy)-2-furanoic acid (preparedas in example 36, step 1 by using 4-chlorophenol in lieu of phenol) inlieu of 2-phenoxybenzoate and by employing the N-hydroxy urea fromexample 42 in lieu of the resultant N-hydroxy urea from example 44. m.p.125°-127° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.32 (1H, s), 8.08 (1H, d, J=9Hz), 7.20-7.33 (4H, m), 7.08 (1H, d, J=4 Hz), 6.31 (2H, s), 5.79 (1H, d,J=4 Hz), 4.20 (1H, septet, J=7 Hz), 3.47 (2H, ABX, J=14.5, 7 Hz), 3.38(2H, ABX, J=14.5, 7 Hz), 1.12 (3H, d, J=7 Hz); MS (M+H)⁺ =338; (M+NH₄)⁺=355. Analysis calc'd for C₁₅ H₁₆ N₃ O₅ F: C, 53.41; H, 4.78; N, 12.46;Found: C, 53.02; H, 4.66; N, 12.27.

EXAMPLE 61 Preparation of N-Hydroxy-N-2-((5-(4-fluorophenoxy)fur-2-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 5-(4-fluorophenoxy)-2-furanoic acid (preparedas in example 36, step 1 by using 4-fluorophenol in lieu of phenol) inlieu of 3-phenoxybenzoate. m.p. 176°-178° C.; ¹ H NMR (300 MHz,DMSO-d₆); 9.29 (1H, s), 8.22 (1H, t, J=5 Hz), 7.20-7.32 (4H, m), 7.09(2H, d, J=3 Hz), 6.36 (2H, s), 5.92 (1H, d, J=3 Hz), 3.30-3.49 (4H, m);MS (M+H)⁺ =324; (M+NH₄)⁺ =341. Analysis calc'd for C₁₄ H₁₄ N₃ O₅ F C,52.02; H, 4.36; N, 13.00; Found: C, 51.60; H, 4.36; N, 12.734.

EXAMPLE 62 Preparation of N-Hydroxy-N-2-((3-(4-fluorophenylsulfonyl)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 4-(4-chlorophenylsulfonyl)benzoate in lieu of3-phenoxybenzoate. m.p. 183°-186° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31(1H, s), 8.22 (1H, t, J=5 Hz), 8.07 (2H, d, J=9.0Hz), 8.01 (4H, d,J=9.0Hz), 7.72 (2H, d, J=9.0Hz), 6.33 (2H, s), 3.38-3.55 (4H, m); MS(M+H)⁺ =399. Analysis calc'd for C₁₆ H₁₆ ClN305S: C, 48.31; H, 4.05; N,10.56; Found: C, 48.64; H, 4.64; N, 9.13.

EXAMPLE 63 Preparation of N-Hydroxy-N- 2-((benzob!furan-2-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing benzo b!furan-2-carboxylic acid in lieu of3-phenoxybenzoate. m.p. 181°-182° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.33(1H, s), 8.65 (1H, t, J=5 Hz), 7.78 (1H, d, J=7.0 Hz), 7.65 (1H, d,J=7.0 Hz), 7.52 (1H, s), 7.47 (1H, t, J=7.0 Hz), 7.33 (1H, t, J=7.0 Hz),6.37 (2H, s), 3.42-3.55 (4H, m); MS (M+H)⁺ =264. Analysis calc'd for C₁₂H₁₃ N₃ O₄ : C, 54.75; H, 4.98; N, 15.96; Found: C, 54.69; H, 5.01; N,15.88.

EXAMPLE 64 Preparation of N-Hydroxy-N- 2-((4-chlorobenzob!thien-2-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing benzo b!thiophene-2-carboxylic acid in lieu of3-phenoxybenzoate. m.p. 181°-184° C. with decomposition; ¹ H NMR (300MHz, DMSO-d₆); 9.34 (1H, s), 8.88 (1H, t, J=5 Hz), 8.20 (1H, s), 8.03(1H, d, J=8.0 Hz), 7.54 (1H, d, J=8.0 Hz), 7.47 (1H, t, J=8.0 Hz), 6.37(2H, s), 3.42-3.55 (4H, m); MS (M+H)⁺ =264. Analysis calc'd for C₁₂ H₁₂ClN₃ OS: C, 45.94; H, 3.86; N, 13.39; Found: C, 45.78; H, 3.62; N,12.96.

EXAMPLE 65 Preparation of N-Hydroxy-N-2-((3-benzoylbenzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 51, but employing 3-benzoylbenzoic acid in lieu of3-phenoxybenzoate. m.p. 168°-170° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.32(1H, s), 8.70 (1H, t, J=5 Hz), 8.20 (1H, br s), 8.12 (1H, d, J=8.0),7.88 (1H, d, J=8.0), 7.55-78 (6H, m), 6.35 (2H, s), 3.42-3.55 (4H, m);MS (M+H)⁺ =328, (M+NH₄)⁺ =350. Analysis calc'd for C₁₇ H₁₇ N₃ O₄ : C,62.38 H, 5.23; N, 12.84; Found: C, 62.01; H, 5.26; N, 12.60.

EXAMPLE 66 Preparation of N-Hydroxy-N-2-((4-(1-phenylethyloxy)benzoyl)amino)ethyl!urea

The reaction flask was charged with ethyl 4-hydroxybenzoate (10 g, 60mmol), 1-bromoethylbenzene (11.5 g, 60 mmol), and K₂ CO₃ (12.4 g, 90mmol) in dry methylethylketone and the resulting mixture was refluxedfor 44 h. After cooling, the reaction mixture was partitioned betweenethyl acetate and water. The aqueous layer was extracted with ethylacetate. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo to provide the corresponding phenyl ethyl ester.

The ester (17.49 g, 60 mmol) was dissolved in ethanol (250 mL) and a 1Msolution of LiOH (240 mL, 240 mmol) was added. After stirring at ambienttemperature for 20 h, the reaction was acidified with 2M aqueous HCl togive a precipitate which was collected by vacuum filtration. The solidwas recrystallized from cold (-20° C.) ether to provide thecorresponding acid (4.21 g, 29%).

The title compound was obtained following the procedures described inExample 2, but employing 4-(1-phenylethyloxy)benzoic acid in lieu of3-phenoxybenzoate. m.p. 164°-166° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31(1H, s), 8.26 (1H, br t, J=5.5 Hz), 7.66-7.70 (2H, m), 7.22-7.44 (5H,m), 6.92-6.96 (2H, m), 6.30 (2H, br s), 5.59 (1H, q J+6.5 Hz), 3.31-3.50(4H, m), 1.56 (3H, d, J=6.5 Hz); MS (M+H)⁺ =344. Analysis calc'd for C₁₈H₂₁ N₃ O₄ : C, 62.96; H, 6.16; N, 12.24; Found: C, 62.56; H,6.20; N,12.12.

EXAMPLE 67 Preparation of N-Hydroxy-N-2-((3-(1-phenylethyloxy)benzoyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 66, but employing ethyl 3-hydroxybenzoate in lieu of ethyl4-hydroxybenzoate. m.p. 164°-165° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.32(1H, s), 8.40 (1H, br t, J=5.5 Hz), 7.21-7.45 (8H, m), 7.01-7.07 (1H,m), 6.32 (2H, br s), 5.56 (1H, q J=6.5 Hz), 3.30-3.52 (4H, m), 1.56 (3H,d, J=6.5 Hz); MS (M+H)⁺ =344; (M+NH₄)⁺ =361. Analysis calc'd for C₁₈ H₂₁N₃ O₄ : C, 62.96; H, 6.16; N, 12.24; Found: C, 62.52; H, 6.16; N, 12.27.

EXAMPLE 68 Preparation of N-Hydroxy-N-2-(((4-(1-phenylethoxy)phenyl)propion-2-yl)amino)ethyl!urea

Methyl 4-hydroxyphenylacetate (15 g, 90.3 mmol) was dissolved in dryDMSO (100 mL) and potassium t-butoxide (10.7 g, 90.3 mmol) was addedportionwise. The resulting solution was stirred for 0.5 h at ambienttemperature and 1-bromoethylbenzene (12.7 g, 90.3 mmol)was added in adropwise fashion. The reaction was stirred at ambient temperature for 18h and partitioned between aqueous ammonium chloride and ether/hexanes(3:1, v:v). The aqueous layer was extracted with the same solvent system(2×) and the organic layers combined, dried (MgSO₄), filtered, andconcentrated under vacuum. The purified alkylation adduct (16.21 g,66%)was obtained by FAC (600 g silica gel, 1:9 ether/pentanes).

The alkylation adduct (15 g, 55.55 mmol) was added to a preformedsolution of LDA (61 mmol) in dry THF (500 mL) at -78° C. The resultingsolution was stirred at -78° C. for 0.5 h and methyl iodide was added tothe reaction mixture. The reaction was permitted to warm slowly to 0° C.and quenched by adding excess saturated aqueous ammonium chloride. Thetwo-phased solution was extracted (2×, ethyl acetate). The combinedorganic layers were washed (1×, 10% aqueous HCl; 1×, saturated aqueousNaHCO₃ ; 1×, brine), dried (MgSO₄), filtered and concentrated in vacuoto provide the unpurified alkylation adduct (15.8 g,˜100%) which wascarried on without further purification.

Hydrolysis was carried out as described in example 66 to provide thecorresponding acid which was convened to the title compound as describedin example 2. m.p. 163°-168° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.23 (1H,s), 7.82-7.88 (1H, m), 7.20-7.41 (2H, m), 7.07-7.12 (2H, m), 6.78-6.82(2H, m), 6.38 (2H, br s), 5.44 (1H, q, J=6.5 Hz), 3.03-3.48 (5H, m),1.52 (3H, d, J=6.5 Hz), 1.22 (3H, d, J=7.0 Hz); MS (M+H)⁺ =372. Analysiscalc'd for C₂₀ H₂₅ N₃ O₄ (0.25 H₂ O): C, 63.90; H, 6.83; N, 11.18;Found: C, 63.73; H, 6.72; N, 11.11.

EXAMPLE 69 Preparation of N-Hydroxy-N-2-(((3-(1-phenylethoxy)phenyl)propion-2-yl)amino)ethyl!urea

The title compound is obtained following the procedures described inExample 69, but employing ethyl 3-hydroxyphenylacetic acid in lieu ofmethyl 4-hydroxyphenylacetic acid.

EXAMPLE 70 Preparation of N-Hydroxy-N-2-(((2-(1-phenylethoxy)phenyl)propion-2-yl)amino)ethyl!urea

The title compound is obtained following the procedures described inExample 69, but employing ethyl 2-hydroxyphenylacetic acid in lieu ofmethyl 4-hydroxyphenylacetic acid.

EXAMPLE 71 Preparation of N-Hydroxy-N-2-((3-phenoxyphenoxyacetyl)amino)ethyl!urea

t-Butyl (3-phenoxy)phenoxyacetate was prepared following the alkylationprocedure as described in example 66 using 3-phenoxyphenol and acetonein lieu of ethyl 4-hydroxybenzoate and methylethylketone.

The t-butyl ester was removed by treatment of the phenoxyacetate (5 g,16.7 mmol) with equal volumes (67 mL) of TFA and dichloromethane andambient temperature for three hours. The volatiles were removed invacuo. The resulting oil was taken up in toluene and concentrated (2cycles), then taken up in dichloromethane and concentrated (1×) toremove excess trifluoroacetic acid to give the corresponding acid as adark oil which was carried on without further purification.

The title compound was prepared as in example 2 employing3-phenoxyphenoxyacetic acid prepared as described in example 72 in lieuof 3-phenoxybenzoic acid. m.p. 153°-155° C.; ¹ H NMR (300 MHz, DMSO-d₆);9.30 (1H, s), 8.08 (1H, t, J=6.0 Hz), 7.26-7.45 (3H, m), 7.12-7.19 (2H,m), 7.00-7.06 (2H, m), 6.71-6.77 (1H, m), 6.57-5.62 (2H, m), 6.32 (2H,br s), 4.45 (2H, s), 3.25-3.43 (4H, m); MS (M+H)⁺ =346; (M+NH₄)⁺ =363.Analysis calc'd for C₁₇ H₁₉ N₃ O₅ : C, 59.12; H, 5.54; N, 12.17; Found:C, 58.79; H, 5.50; N, 12.60.

EXAMPLE 72 Preparation of N-Hydroxy-N-2-((4-phenoxyphenoxyacetyl)amino)ethyl!urea

The title compound is obtained following the procedures described inExample 72, but employing 4-phenoxyphenol in lieu of 3-phenoxyphenol.

EXAMPLE 73 Preparation of N-Hydroxy-N-2-((2-phenoxyphenoxyacetyl)amino)ethyl!urea

The title compound is obtained following the procedures described inExample 72, but employing 2-phenoxyphenol in lieu of 3-phenoxyphenol.

EXAMPLE 74 Preparation of N-Hydroxy-N'-methyl-N-2-((quinolin-2-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 2-quinolinecarboxylic acid in lieu of3-phenoxybenzoate and MeNCO in lieu of TMSNCO. m.p. 158°-159° C.; ¹ HNMR (300 MHz, DMSO-d₆); 9.35 (1H, s), 8.93 (1H, m), 8.57 (1H, d, J=8.5Hz), 8.06-8.19 (3H m), 7.85-7.91 (1H, m), 7.70-75 (1H, m), 6.98 (1H, q,J=5.0 Hz), 3.52-3.59 (4H, m), 2.57 (3H, d, J=5.0 Hz); MS (M+H)⁺ =289.Analysis calc'd for C₁₄ H₁₆ N₄ O₃ : C, 58.32 H, 5.59; N, 19.43; Found:C, 58.34; H, 5.60; N, 19.47.

EXAMPLE 75 Preparation of N-Hydroxy-N-2-((quinolin-2-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing TMSNCO in lieu of MeNCO. m.p. 189°-190° C.; ¹ HNMR (300 MHz, DMSO-d₆); 9.42 (1H, s), 8.96 (1H, m), 8.58 (1H, d, J=8.5Hz), 8.07-8.19 (3H, m), 7.84-7.91 (1H, m), 7.70-75 (1H, m), 6.39 (2H,s), 3.54-3.59 (4H, m); MS (M+H)⁺ =275. Analysis calc'd for C₁₃ H₁₄ N₄ O₃: C, 56.93 H, 5.15; N, 20.43; Found: C, 56.99; H, 5.19; N, 20.24.

EXAMPLE 76 Preparation of N-Hydroxy-N-2-(((3-(6-methoxynaphth-2-yl)-2-methyl-prop-2-enyl)carbonyl)amino)ethyl!urea

To an ice-cooled, magnetically stirred solution of the6-methoxy-2-napthylnitrile (10.0 g, 54.6 mmol) in dry THF (100 mL) wasadded dropwise 60 mL of 1M DIBAL in methylene chloride under nitrogen.After 16 h at ambient temperature, the reaction was quenched withmethanol (dropwise addition). The resulting suspension was treated withaqueous citric acid and extracted with EtOAc (3×200 mL). The combinedorganic extracts were dried(MgSO₄), filtered, and concentrated to givethe corresponding aldehyde (used directly in the next step).

To a magnetically stirred solution of the aldehyde in dry THF (150 mL)was added (carbethoxyethylidene)triphenylphosphorane(18.1 g, 49.9 mmol)in several portions over 2 h. After 16 h, the reaction was concentratedand hexane was added to precipitate the triphenylphosphine oxide, whichwas removed by vacuum filtration and washed with hexane. The filtratewas chromatographed (100 g silica gel, EtOAc-hexane (20:80)) to give thedesired (E)-α,β-unsaturated ester (10.0 g, 68%).

To a magnetically stirred solution of the ester (6.26 g, 23.2 mmol) inTHF (60 mL) and isopropanol (60 mL) was added dropwise 25 mL of 1Maqueous LiOH. After 1 h, the reaction was acidified with aqueous citricacid and extracted with EtOAc (4×100 mL). The combined organic extractswere dried(MgSO4), filtered, and concentrated to provide thecorresponding acid (4.64 g, 82%).

The title compound was obtained following the procedures described inExample 2, but employing acid prepared above in lieu of 3-phenoxybenzoicacid. m.p. 174°-176° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.18 (1H, s), 8.02(1H, t, J=5.5 Hz), 7.85 (3H, m), 7.50 (1H, dd, J=8.5,1.5), 7.35 (2H, m),7.18 (1H, dd, J=9,2.5), 6.53 (2H, s), 3.89 (3H, s), 3.27-3.49 (4H, m),2.10 (3H, d, J=1.5 Hz); MS (M+H)⁺ =344. Analysis calc'd for C₁₈ H₂₁ N₃O₄ : C, 62.96 H, 6.16; N, 12.24; Found: C, 62.80; H, 6.02; N, 12.00.

EXAMPLE 77 Preparation of N-Hydroxy-N-2-((3-phenylpropionyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing dihydrocinnamate in lieu of 3-phenoxybenzoicacid. m.p. 165°-167° C.; ¹ H NMR (300 MHz, DMSO-d₆); 7.75 (1H, t, J=5.5Hz), 7.05-7.20 (5H, m), 6.97 (2H, m), 6.43 (2H, s), 3.36 (2H, t, J=7.0Hz), 3.10 (2H, q, J=6.5 Hz), 2.71 (2H, dd, J=8.0,7.5 Hz), 2.26 (2H, dd,J=8.0,7.5 Hz); MS (M+H)⁺ =252. Analysis calc'd for C₁₂ H₁₇ N₃ O₃ : C,57.36 H, 6.82; N, 16.72; Found: C, 57.22; H, 6.71; N, 16.52.

EXAMPLE 78 Preparation of N-Hydroxy-N-2-((3-(4-n-butoxyphenyl)prop-2-enoyl)amino)ethyl!urea

Following the procedure of Meyer (Campaigne, E.; Meyer, W. W. J. Org.Chem. 1962, 27, 2835) 4-butoxybenzaldehyde was converted to methyl4-butoxycinnamate Hydrolysis of the ester to the corresponding acid 1,was completed following the procedure as described in example 77. Thetitle compound was obtained following the procedures described inExample 2, but employing acid prepared above in lieu of 3-phenoxybenzoicacid. m.p. 127°-129° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.31 (1H, s), 8.02(1H, t, J=5.5 Hz), 7.48 (2H, d, J=8.5 Hz), 7.36 (1H, d, J=16.0), 6.96(2H, d, J=8.5 Hz), 6.52 (1H, d, J=16.0), 4.74 (2H, br s), 3.99 (2H, t,J=6.5), 3.45 (2H, t, J=6.0 Hz), 3.24 (2H, q, J=6.0 Hz), 1.70 (2H, m),1.43 (2H, m), 0.93 (3H, t, J=7.5 Hz); MS (M+H)⁺ =322. Analysis calc'dfor C₁₆ H₂₃ N₃ O₄ : C, 59.80 H, 7.21; N, 13.08; Found: C, 59.65; H,7.05; N, 12.90.

EXAMPLE 79 Preparation of N-Hydroxy-N-2-((3-(3-n-butoxyphenyl)prop-2-enoyl)amino)ethyl!urea

The title compound is obtained following the procedures described inExample 79, but employing 3-butoxybenzaldehyde in lieu of4-butoxybenzaldehyde.

EXAMPLE 80 Preparation of N-Hydroxy-N-2-((3-(2-n-butoxyphenyl)prop-2-enoyl)amino)ethyl!urea

The title compound is obtained following the procedures described inExample 79, but employing 2-butoxybenzaldehyde in lieu of4-butoxybenzaldehyde.

EXAMPLE 81 Preparation of N-Hydroxy-N-2-((2-(6-methoxynaphth-2-yl)propionyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing naproxen in lieu of 3-phenoxybenzoate. m.p.161.5°-162.5° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.27 (1H, s), 7.92 (1H, t,J=5.5 Hz), 7.19 (2H, AB, J=9.0 Hz), 7.06 (2H, AB, J=9.0 Hz), 6.31 (2H,s), 3.86 (3H, s), 3.70 (1H, q, J=7.0 Hz), 3.10-3.38 (4H, m), 1.90 (3H,d, J=7.0 Hz); MS (M+H)⁺ =332; (M=NH₄)⁺ =349. Analysis calc'd for C₁₇ H₂₁N₃ O₄ (0.25 H₂ O): C, 60.79 H, 6.45; N, 12.51; Found: C, 60.78; H, 6.34;N, 12.45.

EXAMPLE 82 Preparation of N-Hydroxy-N-2-((2-(4-(2-methylpropyl)phenyl)propionyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing ibuprofen in lieu of 3-phenoxybenzoate. m.p.150.5°-152.5° C.; ¹ H NMR (300 MHz, DMSO-d₆); 9.27 (1H, s), 7.99 (1H, t,J=5.5 Hz), 7.78 (1H, d, J=9.0 Hz), 7.75 (1H, d, J=9.0 Hz), 7.70 (1H, s),7.42 (1H dd, J=9.0,2.0 Hz), 7.27 (1H, d, J=2.0 Hz), 7.13 (1H, dd,J=9.0,2.0 Hz), 6.31 (2H, s), 3.52 (1H, q, J=7.0 Hz), 3.07-3.38 (4H, m),2.39 (2H, d, J=7.0 Hz), 1.79 (1H, septet, J=7.0 Hz), 1.30 (3H, d, J=7.0Hz), 0.84 (6H, d, J=7.0 Hz); MS (M+H)⁺ =308. Analysis calc'd for C₁₆ H₂₅N₃ O₃ : C, 62.52 H, 8.20; N, 13.67; Found: C, 62.69; H, 8.31; N, 13.58.

EXAMPLE 83 Preparation of N-Hydroxy-N-2-((2-(2,6-dichlorophenylamino)phenylacetyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing diclofinac in lieu of 3-phenoxybenzoate. Alactam was the product from the attempted acid chloride formation. Thenormal mitsunobu intermediate was prepared by heating the lactam in thepresence of ethanolamine. m.p. 187°-189° C.; ¹ H NMR (300 MHz, DMSO-d₆);9.31 (1H, s), 8.37 (1H, t, J=5.5 Hz), 8.32 (1H, s), 7.52 (2H, d, J=8.0Hz), 7.18 (1H, rid, J=8.0,1.5 Hz), 7.15 (1H, t, J=8.0 Hz), 7.03 (1H, dd,J=8.0,1.5 Hz), 6.83 (1H, dd, J=8.0,1.5 Hz), 6.31 (2H, s), 6.28 (1H, dd,J=8.0,1.5 Hz), 3.57 (2H, s), 3.40 (2H, m), 3.25 (2H, m); MS (M+H)⁺=397/399/401. Analysis calc'd for C₁₇ H₁₈ N₄ O₃ Cl₂ : C, 51.40 H, 4.57;N, 14.10; Found: C, 51.07; H, 4.45; N, 13.98.

EXAMPLE 84 Preparation of N-Hydroxy-N-2-((2-phenylthiazol-4-oyl)amino)ethyl!urea

The title compound was obtained following the procedures described inExample 2, but employing 2-phenylthiazol-4-carboxylic acid in lieu of3-phenoxybenzoate. m.p. 188°-192° C. with decomposition; ¹ H NMR (300MHz, DMSO-d₆); 9.48 (1H, s), 8.55 (1H, t, J=5 Hz), 8.04-8.07 (2H, m),7.53-7.58 (4H, m), 6.35 (2H, s), 3.45-3.55 (4H, m); MS (M+H)⁺ =307,(M+NH₄)⁺ =324. Analysis calc'd for C₁₃ H₁₄ N₄ O₃ S (0.75 H₂ O): C,49.07; H, 4.45; N, 17.18; Found: C, 48.82; H, 4.88; N, 17.52.

EXAMPLE 85 Preparation of (d,l)-N-Hydroxy-N-3-((tert-butyoxycarbonyl)amino)prop-2-yl!urea

A one liter roundbottom flask was charged with dichloromethane (450 mL)and di-t-butyldicarbonate (11.04 g, 0.146 mol). A dichloromethane (100mL) solution of 1-amino-2-propanol (29 g, 0.154 mol) was added dropwise.The resulting mixture was stirred one h at room temperature andpartitioned between 10% aqueous HCl and dichloromethane. The aqueouslayer was extracted (2×) with dichloromethane. The combined organicextracts were washed (1×, sat'd NaHCO₃ ; 1×, brine), dried (MgSO₄),filtered and concentrated in vacuo to give a light yellow liquid (26.5g, 103%). The resulting N-Boc-1-amino-2-propanol was carried on withoutfurther purification.

A one liter roundbottom flask was charged with N-Boc-1-amino-2-propanol(26.42 g, 0.0151 mol), triphenylphosphine (41.4 g, 0.158 mol), andN,O-bisphenyloxycarbonylhydroxylamine (43.2 g, 0.158 mol), and dry THF(550 mL). The solution was cooled to 0° C., and diethylazodicarboxylate(24.9 mL, 0.158 mol) was added in THF (50 mL). The reaction was stirredone hour after removing the cooling bath, and concentrated under vacuum.Chromatographic purification is enhanced by adding dichloromethane (200mL) and concentrating in vacuo twice to remove THF before columnchromatography (400 g silica gel, 15% EtOAc/Hex) to provideN,O-bisphenyloxycarbonyl-t-butyloxycarbonylamino-2-propylhydroxylamine(54.4 g, 80%).

A resealable tube was charged with a solution of theN,O-diphenyloxycarbonylpropylhydroxylamine (22 g, 0.051 mol, preparedabove) in the minimum volume of ether (10 mL). The solution was cooledto -23° C. and liquid ammonia (100 mL) was condensed into the resealabletube. The tube was sealed, the cooling bath removed, and the reactionstirred overnight (˜17 h). After cooling the tube, the seal was removedand the ammonia evaporated to give a brown residue which was purified bychromatography (400 g silica gel, 40% EtOAc/CH₂ Cl₂ (2.5 L) then 5%MeOH/CH₂ Cl₂ (2 L)) to provide a white solid which was triturated withether to provide the title compound (6.54 g, 55%). m.p. 158°-159° C.; ¹H NMR (300 MHz, DMSO-d₆); 8.33 (1H, s), 5.13 (2H, br s), 5.0 (1H, br m),4.33 (ddd, J=14.5, 12, 9 Hz; MS (M+H)⁺ =234, (M+NH₄)⁺ =251. Analysiscalc'd for C₁₃ H₁₄ N₄ O₃ S (0.75 H₂ O): C, 46.86; H, 8.21; N, 18.01;Found: C, 46.86; H, 8.54; N, 18.13.

EXAMPLE 86 Preparation of N-Hydroxy-N-3-((5-(4-fluorophenoxy)furan-2-oyl)amino)prop-2-yl!urea

The title compound was obtained following the procedures described inExample 51, but employing2-N-Hydroxy-1-t-butyloxycarbonylamino-propylurea (prepared as describedin example 85) in lieu of(S)-N-Hydroxy-2-t-butyloxycarbonylamino-propylurea. M.p. 180-181° C.; ¹H NMR (300 MHz, DMSO-d₆); 8.78 (1H, s), 8.14 (1H, t, J=7.5,7.5 Hz),7.20-7.33 (4H, m), 7.08 (1H, d, J=4 Hz), 6.34 (2H, s), 5.79 (1H, d, J=4Hz), 4.20 (1H, br sextet, J=7.5 Hz), 3.32 (2H, dt, J=14.5, 7, 7 Hz),3.14 (2H, ddd, J=14.5, 6, 9 Hz), 0.97 (3H, d, J=7 Hz); MS (M+H)⁺ =338.Analysis calc'd for C₁₅ H₁₆ N₃ O₅ F: C, 53.41; H, 4.78; N, 12.46; Found:C, 53.43; H, 4.55; N, 12.47.

EXAMPLE 87 Preparation ofN-Hydroxy-N-2-((2-(1-phenylethyloxy)benzoyl)amino)ethyl!urea

The title compound was prepared following the method of Example 66 butemploying ethyl 2-hydroxybenzoate in lieu of ethyl 4-hydroxybenzoate.

EXAMPLE 88 Preparation of N-Hydroxy-N-4-((5-(4-fluorophenoxy)furan-2-oyl)amino)but-2yl!urea

The title compound was obtained following the procedures described inExample 2, but employing 5-(4-fluorophenoxy)-2-furanoic acid in lieu of3-phenoxybenzoic acid and 1-aminobutan-3-ol in lieu of ethanol amine.m.p. 161°-163° C.; ¹ H NMR (300 MHz, DMSO-d₆); 8.90 (1H, s), 8.14 (1H,t, J=7.5,7.5 Hz), 7.20-7.33 (4H, m), 7.08 (1H, d, J=4 Hz), 6.30 (2H, s),5.79 (1H, d, J=4 Hz), 4.13 (1H, br sextet, J=7.5 Hz), 3.27 (2H, br m),3.10 (2H, br m), 1.72 (1H, sextet, J=7.5 Hz), 1.53 (1H, sextet, J=7.5Hz), 1.01 (3H, d, J=7.5 Hz); MS (M+H)⁺ =352, (M+NH₄)⁺ =251. Analysiscalc'd for C₁₆ H₁₈ N₃ O₅ F: C, 54.70; H, 5.16 N, 11.46; Found: C, 54.14;H, 5.24; N, 11.46.

The substituted amide-linked N-hydroxyureacompounds of Examples 89-128as shown in Table 3 are prepared by the method used for Example 2substituting m-phenoxybenzoic acid with the requisite substitutedbenzoic acid derivative which can be prepared according to thealkylation procedure outlined in example 23.

                  TABLE 3    ______________________________________    Substituted Hydroxybenzoate Amide-linked N-Hydroxyureas     ##STR9##    Example    R.sub.1    ______________________________________     89        (CH.sub.2).sub.2 CH.sub.3     90        (CH.sub.2).sub.3 CH.sub.3     91        (CH.sub.2).sub.4 CH.sub.3     92        (CH.sub.2).sub.5 CH.sub.3     93        CH.sub.2 CH(CH.sub.3).sub.2     94        (CH.sub.2).sub.2 CH(CH.sub.3).sub.2     95        (CH.sub.2).sub.3 CH(CH.sub.3).sub.2     96        (CH.sub.2).sub.4 CH(CH.sub.3).sub.2     97        CH.sub.2 CHCH.sub.2     98    trans-CH.sub.2 CHCHCH.sub.3     99    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    100        CH.sub.2 CHC(CH.sub.3)CH.sub.3    101        CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    102        CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    103        (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    104        (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    105        CH.sub.2 -2-pyridyl    106        CH.sub.2 -3-pyridyl    107        CH.sub.2 -4-pyridyl    108        CH.sub.2 -2-furyl    109        CH.sub.2 -3-furyl    110        CH.sub.2 -2-thienyl    111        CH.sub.2 -3-thienyl    112        CH.sub.2 -2-benzo b!thienyl    113        CH.sub.2 -2-benzo b!furyl    114        CH.sub.2 -2-thiazoyl    115        CH.sub.2 -2-imidazoyl    116        CH(CH.sub.3)-2-pyrimidyl    117        CH(CH.sub.3)-2-pyridyl    118        CH(CH.sub.3)-3-pyridyl    119        CH(CH.sub.3)-4-pyridyl    120        CH(CH.sub.3).sub.2 -2-furyl    121        CH(CH.sub.3)-3-furyl    122        CH(CH.sub.3)-2-thienyl    123        CH(CH.sub.3)-3-thienyl    124        CH(CH.sub.3)-2-benzo b!thienyl    125        CH(CH.sub.3).sub.2 -2-benzo b!furyl    126        CH(CH.sub.3)-2-thiazoyl    127        CH(CH.sub.3)-2-imidazoyl    128        CH(CH.sub.3)-2-pyrimidyl    ______________________________________

The substituted benzoate amide-linked N-hydroxyurea compounds ofExamples 129-153 shown in Table 4 were prepared following the proceduresdescribed in example 51 by employing the appropriate aryl acid andsubstituted N-hydroxy-N- 2-((tert-butoxycarbonyl)amino)ethyl!urea(examples 42, 43, 44). The starting 3-aryloxy- and 3-thioaryloxy benzoicacids were either commercially available or were prepared by an Ullmancoupling (see Fanta, F. E. Chem. Rev. 1946, 38, 139) between theappropriate phenol/thiophenol and aryl halide. The 5-thioaryloxy and5-aryloxy 2-furoic acid derivatives were prepared as described inexample 36 for the preparation of 5-phenoxy-2-furoic acid fromcommercially available precursors.

                                      TABLE 4    __________________________________________________________________________    Substituted Benzoate Amide-linked N-Hydroxyureas     ##STR10##    Ex. Ar.sup.1                X   Ar.sup.2 R.sup.1                                  R.sup.2                                      mp    __________________________________________________________________________    129 Phenyl  O   1,3-benzoyl                             (S)-Me                                  H   132-134    130 4-Fluorophenyl                O   1,3-benzoyl                             (S)-Me                                  H   115-117    131 4-Fluorophenyl                O   4-MeO-1,3-                             H    H   148-149                    benzoyl    132 4-methylphenyl                O   2,5-furanoyl                             H    Me  169-171    133 4-Fluorophenyl                S   2,5-furanoyl                             H    H   158-160    134 4-chlorophenyl                O   1,3-benzoyl                             H    Me  186-189    135 4-Fluorophenyl                O   4-Br-2,5-                             H    H   194-197                    furanoyl          decomp    136 4-Fluorophenyl                S   2,5-furanoyl                             (R)-Me                                  H   115-116    137 4-Fluorophenyl                O   4-Br-2,5-                             (R)-Me                                  H   153-156                    furanoyl    138 4-Fluorophenyl                S   2,5-furanoyl                             H    Me  172-175    139 4-Fluorophenyl                S   2,5-furanoyl                             (R)-Me                                  H   161-164    140 4-Fluorophenyl                O   2,5-furanoyl                             (R)-i-Pr                                  H   150-152    141 Phenyl  S   2,5-     H    Me  174-180                    thiophenoyl       decomp    142 4-Fluorophenyl                O   2,5-furanoyl                             H    (R)-Me                                      182-183    143 4-Fluorophenyl                O   2,5-furanoyl                             H    (S)-Me                                      177-178    144 n-Butyl O   1,3-benzoyl                             H    Me  194-195    145 2,4-    O   2,5-furanoyl                             H    Me  183-184        Difluorophenyl    146 Phenyl  O   2,5-furanoyl                             H    Me  153-155    147 4-Methylphenyl                O   2,5-furanoyl                             H    Me  182-184    148 4-Fluorophenyl                O   2,5-     H    Me  193-194                    thiophenoyl    149 Napth-2-yl                O   2,5-furanoyl                             H    Me  193-196    150 3,4-    O   2,5-furanoyl                             H    Me  201-202        Difluorophenyl    151 4-Cyanophenyl                O   2,5-furanoyl                             H    Me  164-170    152 3-pyridyl                O   2,5-furanoyl                             H    Me  decomp    153 4-Chlorophenyl                O   1,3-benzoyl                             (S)-Me                                  H   155-156    __________________________________________________________________________

EXAMPLE 154 Preparation of N-Hydroxy-N-2-(3-(4-bromophenyl)propenoyl)amino!ethyl urea

Following the procedure outlined in example 51 but employing4-bromocinammoyl chloride in lieu of 2-phenoxybenzoyl chloride providedthe title compound as a colorless solid after chromatographicpurification. m.p. 143°-145° C.; ¹ H NMR (300 MHz, D₆ -DMSO) 9.30 (1H,s), 8.16 (1H, t, J=5.5,5.5 Hz), 7.61 (2H, d, J=8.5 Hz), 7.51 (2H, d,J=8.5 Hz), 7.39 (1H, d, J=16 Hz), 6.70 (1H, d, J=16 Hz), 6.25 (2H, s),3.43 (2H, m), 3.36 (2H, m). Analysis calc'd for C12H₁₄ N₃ O₃ Br: C,43.92; H, 4.30; N, 12.80; Found: C, 43.70; H, 4.35; N, 12.60.

EXAMPLE 155 Preparation of N-Hydroxy-N-2-((3-phenylpropenoyl)amino!ethylurea

Following the procedure outlined in example 51 but employing cinammoylchloride in lieu of 2-phenoxybenzoyl chloride provided the titlecompound as a colorless solid after chromatographic purification. m.p.160°-162° C.; ¹ H NMR (300 MHz, D₆ -DMSO) 9.32 (1H, s), 8.14 (1H, t,J=5.5,5.5 Hz), 7.56 (2H, dd, J=8.5,1 Hz), 7.35-7.46 (4H, m), 6.63 (1H,d, J=16 Hz), 6.32 (2H, s), 3.43 (2H, br t, J=6.5 Hz), 3.36 (2H, br t,J=6.5 Hz). Analysis calc'd for C₁₂ H₁₅ N₃ O₃ : C, 57.82; H, 6.07; N,16.86; Found: C, 57.60; H, 5.91; N, 16.79.

EXAMPLE 156 Preparation of (R)-N-Hydroxy-N-2-(3-(4-bromophenyl)propenoyl)amino!propyl urea

Following the procedure outlined in example 78052 but employing(R)-N-hydroxy-N- 2-((tert-butoxycarbonyl)amino)propyl!urea in lieu ofN-hydroxy-N- 2-((tert-butoxycarbonyl) amino)ethyl!urea provided thetitle compound as a colorless solid after recrystallization frommethanol. m.p. 192°-193.5° C.; ¹ H NMR (300 MHz, D₆ -DMSO) 9.30 (1H, s),8.08 (1H, d, J=9 Hz), 7.61 (2H, d, J=8.5 Hz), 7.51 (2H, d, J=8.5 Hz),7.39 (1H, d, J=16 Hz), 6.63 (1H, d, J=16 Hz), 6.28 (2H, s), 4.16 (1H,septet, J=7.5 Hz), 3.36 (2H, d, J=7.5 Hz), 1.09 (3H, d, J=7.5 Hz); MS(M+NH₄)⁺ =359. Analysis calc'd for C₁₃ H₁₆ N₃ O₃ Br: C, 45.63; H, 4.71;N, 12.28; Found: C, 45.33; H, 4.69; N, 12.05.

EXAMPLE 157 Preparation of (d,l)-N-Hydroxy-N-3-(3-(4-bromophenyl)propenoyl)amino!prop-2-yl urea

Following the procedure outlined in example 78052 but employingN-hydroxy-N- 3-((tert-butyoxycarbonyl)amino)prop-2-yl!urea in lieu ofN-hydroxy-N- 2-((tert-butoxycarbonyl) amino)ethyl!urea provided thetitle compound as colorless solid after recrystallization from methanol.m.p. 199°-200.5° C.; ¹ H NMR (300 MHz, D₆ -DMSO) 8.88 (1H, s), 8.08 (1H,d, J=9 Hz), 8.17 (1H, t, J=6 Hz), 7.61 (2H, d, J=8.5 Hz), 7.53 (2H, d,J=8.5 Hz), 7.41 (1H, d, J=16 Hz), 6.69 (1H, d, J=16 Hz), 6.30 (2H, s),4.18 (1H, sextet, J=7.5 Hz), 3.25 (2H, t, J=7.5 Hz), 0.98 (3H, d, J=7.5Hz); MS (M+H)⁺ =342, (M+NH₄)⁺ =359. Analysis calc'd for C₁₃ H₁₆ N₃ O₃Br(0.2 H₂ O): C, 45.15; H, 4.78; N, 12.15; Found: C, 44.89,; H, 4.78; N,12.15.

EXAMPLE 158 Preparation ofN-Hydroxy-N-2-((3-(4-bromophenyl)propanoyl)amino!ethyl urea

Following the procedure outlined in example 51 but employing3-(4-bromophenyl)propionyl chloride (prepared by reduction of4-bromocinnamic acid over 5% Pt/C in ethyl acetate at 4 atm of hydrogenand subsequent conversion to the acid chloride with oxalyl chloride) inlieu of 2-phenoxybenzoyl chloride provided the title compound as acolorless solid after recrystallization from methanol. m.p. 177.5°-179°C.; ¹ H NMR (300 MHz, D₆ -DMSO) 9.27 (1H, s), 7.87 (1H, t, J=5.5,5.5Hz), 7.46 (2H, d, J=8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 6.30 (2H, s), 3.43(2H, br t, J=7.5 Hz), 3.20 (2H, br q, J=7.5 Hz), 2.77 (2H, t, J=7.5 Hz),2.35 (2H, t, J=7.5 Hz); MS (M+H)⁺ =330/332. Analysis calc'd for C12H₁₆N₃ O₃ Br(0.1 H₂ O): C, 43.42; H, 4.92; N, 12.66; Found: C, 43.07; H,4.64; N, 12.54.

EXAMPLE 159 Preparation of N-Hydroxy-N-2-(3-(3-(4-chlorophenoxy)phenyl)propynoyl)amino!ethyl urea

Ethyl 3-(3-(4-chlorphenoxy)phenyl)propynoate was prepared by addinganhydrous powdered K₂ CO₃ (4.14 g, 30 mmol) portionwise to a suspensionof 3-(4-chlorophenoxy)benzaldehyde (2.33 g, 10 mmol) and ethyl2-iodo-2-(triphenylphosphonium)acetate iodide (8.43 g, 14 mmol) in drymethanol (60 mL). The reaction was stirred overnight at ambienttemperature, diluted with a 1:1 solution of ethyl acetate and hexanes,and filtered. The filtrate was concentrated and chromatographed onsilica gel (100 g) using 10% ethyl acetate/hexanes and then 20% ethylacetate/hexanes as the eluant. The alkynoic ester was convened to themixed anhydride by first hydrolyzing the ester (301 mg, 1 mmol) byexposure to an aqueous solution of LiOH (1.1 mL, 1M solution) inabsolute ethanol (5 mL) at ambient temperature. The reaction was judgedcomplete after 45 minutes and the volatiles were removed under reducedpressure. The residue was vacuum dried, suspended in dichloromethane (8mL), and treated with isobutyl chlorformate (0.14 g, 1 mmol) under anargon atmosphere. After 30 minutes N-hydroxy-N- 2-((tert-butoxycarbonyl)amino)ethyl!urea (0.22 g, 1 mmol) and triethylamine (0.126 g, 1.25 mmol)were added and the resulting mixture was stirred for 1 h at ambienttemperature and concentrated under vacuum. The residue was dissolved indichloromethane(8 mL), glacial acetic acid (1 mL), and boron trifluorideetherate (0.25 mL). After 30 minutes the reaction was carefullyneutralized with excess saturated aqueous sodium bicarbonate andextracted with ethyl acetate. The title compound was obtained as acolorless solid after chromatographic purification over silica gel usingethyl acetate as the eluant. m.p. 140°-142° C.; ¹ H NMR (300 MHz, D₆-DMSO) 9.28 (1H, s), 8.01 (1H, t, J=5.5,5.5 Hz), 7.00-7.5 (4H, m), 7.46(2H, d, J=8.5 Hz), 7.10 (2H, d, J=8.5 Hz), 6.30 (2H, s), 3.2-3.4 (4H,m); MS (M+H)⁺ =374. Analysis calc'd for C₁₈ H₁₆ N₃ O₄ Cl: C, 57.84; H,4.31; N, 11.24; Found: C, 57.60; H, 4.25; N, 11.10.

EXAMPLE 160 Preparation of N-Hydroxy-N-2-N"-benzyloxycarbonyl-((3-phenoxyphenyl) methyl)amino!ethyl urea

Step 1: Preparation of N-2-((3-phenoxyphenyl)methyl)-2-aminoethanol.

The title compound was prepared following the procedure described inexample 37, step 1, but employing 2-aminoethanol in lieu of N-methylethanolamine and employing 3-phenoxybenzaldehyde in lieu of3-(4-chlorophenoxy)benzaldehyde.

Step 2; Preparation ofN-benzyloxycarbonyl-N-((3-phenoxyphenyl)methyl)-2-aminoethanol.

The resulting compound (2.78 g, 11.4 mmol) from step 1 and tritheylamine(2.4 mL, 17.2 mmol) were dissolved in dichloromethane (30 mL). To thesolution was added carbobenzyloxychloride (1.9 mL, 12.6 mmol) indichloromethane (15 mL). After 0.5 h the reaction was partitionedbetween 10% aqueous HCl and s dichloromethane. The layers were separatedand the aqueous layer was extracted with dichloromethane. The combinedorganic layers were washed (1×, saturated sodium bicarbonate; 1×,brine), dried over MgSO₄, and concentrated under vacuum to provide thetitle compound (3.99 g, 93%) as a golden oil. The Cbz-protectedaminoalcohol was of sufficient purity to carry on without furtherpurification.

Step 3: Preparation of N-Hydroxy-N-2-N",benzyloxycarbonyl-((3-phenoxyphenyl)methyl)amino!ethyl urea

The title compound was obtained following the procedures described inExample 2, but employingN-benzyloxycarbonyl-N-((3-phenoxyphenyl)methyl)-2-aminoethanol (preparedas described above) in lieu of the amide alcohol. m.p. 91.5°-93° C.; ¹ HNMR (300 MHz, D₆ -DMSO; a 1:1 mixture of rotamers were observed forcertain protons in the HNMR) 9.28 and 9.33 (1H, s), 6.83-7.42 (9H, m),6.33 (2H, s),5.05 and 5.12 (2H, br s), 3.30-3.51 (4H, m). Analysiscalc'd for C₂₄ H₂₅ N₃ O₅ : C, 66.20; H, 5.79; N, 9.65; Found: C, 66.16;H, 5.86; N, 9.89.

EXAMPLE 161 Preparation of N-Hydroxy-N-2-(3-phenoxyphenyl)methyl)amino!ethyl urea

The title compound was obtained by exposing N-Hydroxy-N-2-N"-benzyloxycarbonyl-((3-phenoxyphenyl) methyl)amino!ethyl urea (1.26 g,2.89 mmol) to 10% Pd/C (1.26 g) in absolute ehtanol (12 mL) anddioxane/HCL (10 mL, 4.8M HCl) under 1 atm of hydrogen. The reaction wasjudged to be complete after 0.5 h. After purging with nitrogen, thereaction was filtered through celite and the filter cake washed (3×, 15mL 1:1 absolute ethanol:4.8M dioxane HCl). The combined filtrates wereconcentrated under vacuum and the resulting residue partitioned betweenethyl acetate and 10% aqueous sodium hydroxide. The combined organiclayers were washed (3×, brine), dried over NaSO₄, and concentrated undervacuum to provide a light brown waxy solid. Recrystallization from ethylacetate and hexanes provided the title compound (160 mg, 18%) as acolorless solid m.p. 105°-107° C.; ¹ H NMR (300 MHz, D₆ -DMSO; a 1:1mixture of rotamers were observed for certain protons in the HNMR) ca.9.3 (1H, br s), 7.38 (2H, dd, J=9,7 Hz), 7.32 (1H, d, J=7 Hz), 7.13 (1H,q, J=7 Hz), 6.97-7.05 (3H, m), 6.86 (1H, dd, J=7,2 Hz), 6.28 (2H, s),3.40 (2H, t, J=6.5 Hz), 3.32 (2H, br s), 2.67 (2H, t, J=6.5 Hz); MS(M+H)⁺ =302. Analysis calc'd for C₁₆ H₁₉ N₃ O₃ : C, 63.77; H, 6.35; N,13.94; Found: C, 63.51; H, 6.60; N, 13.99.

EXAMPLE 162 Preparation of N-Hydroxy-N-2-(3-(3-(4-chlorophenoxy)phenyl)-transpropenoyl)amino!ethyl urea

Step 1: Preparation of 3-((4-chlorophenoxy)phenyl)propenoate.

To a solution of 3-(4-chlorophenoxy)benzaldehyde (23.3 g, 0.10 mol) indry pyridine (100 mL) was added malonic acid (52.0 g, 0.50 mol) andmorpholine (1.5 mL). The resulting solution was heated at 60° C. for 8h, then stirred at ambient temperature for 48 h. The reaction was pouredinto cold 1% aqueous HCl solution and stirred vigorously for 1.5 h. Theresulting colorless solid was collected by filtration and washed withwater. After drying, the solid was recrystallized from 95% ethanol toprovide the acid (23.1 g, 84%) after drying under vacuum.

Step 2: Preparation of N-Hydroxy-N-2- (3-(3-(4-chlorophenoxy)phenyl)propenoyl)amino!ethyl urea

The title compound was prepared by following the procedures in example51 but employing 3-((4-chlorophenoxy)phenyl) propenoate in lieu of2-phenoxybenzoate. m.p. 160°-162° C.; ¹ H NMR (300 MHz, D₆ -DMSO) 9.31(1H, s), 8.09 (1H, t, J=6 Hz), 7.35-7.47 (5H, m), 7.22 (1H, br s),7.02-7.09 (4H, m), 6.58 (1H, d, J=15.5 Hz), 6.53 (2H, s), 3.53 (2H, t,J=6.5 Hz), ca. 3.32 (2H, m); MS (M+H)⁺ =302. Analysis calc'd for C₁₈ H₁₈N₃ O₄ Cl: C, 57.53; H, 4.83; N, 11.18; Found: C, 57.33; H, 4.60; N,11.01.

EXAMPLE 163 Preparation of N-Hydroxy-N-2-(3-(3-butyloxyphenyl)-trans-propenoyl)amino!ethyl urea

The title compound was prepared by following the procedures in example51 but employing 3-(3-butyloxyphenyl)propenoate in lieu of2-phenoxybenzoate. The starting acid, 3-(3-butyloxyphenyl)propenoate,was prepared from 3-hydroxybenzaldehyde by conversion to3-butyloxybenzaldehyde by the procedure described in example 19. The3-butyloxybenzaldehyde was converted to the corresponding propenoatefollowing the method described in step 1 of Example 162. The titlecompound was obtained as a colorless solid after chromatographicpurification over silica gel using ethyl acetate as the eluant. m.p.159°-160° C.; ¹ H NMR (300 MHz, D₆ -DMSO) 9.32 (1H, s), 8.10 (1H, t, J=6Hz), 7.49 (1H, d, J=15.5 Hz), 7.31 (1H, t, J=8 Hz), 7.10-7.14 (2H, m),6.93 (1H, dt, J=9,1,1 Hz), 6.63 (1H, d, J=15.5 Hz), 6.33 (2H, s), 3.99(2H, t, J=6.5 Hz), 3.43 (2H, m), ca. 3.36 (2H, m), 1.71 (2H, pentet, J=7Hz), 1.44 (2H, sextet, J=7 Hz), 0.93 (3H, t, J=7 Hz); MS (M+H)⁺ =322,(M+NH₄)⁺ =339. Analysis calc'd for C₁₆ H₂₃ N₃ O₄ : C, 59.80; H, 7.21; N,13.08; Found: C, 59.70; H, 7.10; N, 13.00.

EXAMPLE 164 Preparation of N-Hydroxy-N-2-(3-(4-chlorophenoxy)phenyl),3-methyl-trans-propenoyl)amino!ethyl urea

Step 1. Preparation of3-(4-chlorophenoxy)phenyl)-3-methyl-trans-propenoate.

3-(4-chlorophenoxy)benzaldehyde was convened to the correspondingacetophenone derivative (addition of methylmagnesium bromide thenoxidation to the ketone with Jones reagent). The ketone (2.46 g, 10.0mmol) was treated with bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (3.56 g, 11.2 mmol), lithium bromide (1.13 g, 13.0 mmol),and triethylamine (1.8 mL. 13.0 mmol) in dry THF (Synth. Commun. 1990,20(6), 869) to provide the methyl ester of the title compound as amixture of isomers. The pure trans-isomer was obtained by chromatographyover silica gel (100 g) using 5% ethyl acetate:hexanes and then 10%ethyl acetate:hexanes as the eluant. Conversion of the methyl ester (687mg, 2.27 mmol) to the corresponding acid was achieved by hydroysis inethanolic (20 mL) aqueous lithium hydroxide (4 mL of a 1M aqueoussolution).

Step 1. Preparation of N-Hydroxy-N-2-(3-(4-chlorophenoxy)phenyl)-3-methyl-trans-propenoyl)amino!ethyl urea.

The title compound was prepared by following the procedures in example51 but employing 3-(4-chlorophenoxy)phenyl)-3-methyl-trans-propenoate inlieu of 2-phenoxybenzoate. The title compound was obtained as a yellowoil after chromatographic purification over silica gel using ethylacetate as the eluant. ¹ H NMR (300 MHz, D₆ -DMSO) 9.31 (1H, s), 8.03(1H, t, J=6 Hz), 7.40-7.47 (3H, m), 7.31 (1H, br d, J=5.5 Hz), 7.18 (1H,t, J=1,5 Hz), 7.00-7.05 (3H, m), 6.32 (2H, s), 6.21 (1H, d, J=1.5 Hz),3.27-3.43 (4H, m), 2.45 (3H, d, J=1.5 Hz); MS (M+H)⁺ =390, (M+H)⁺ =407.Analysis calc'd for C₁₉ H₂₀ N₃ O₄ Cl: C, 58.54; H, 5.17; N, 10.78;Found: C, 58.30; H, 5.10; N, 10.05.

EXAMPLE 165 Preparation of N-Hydroxy-N-2-(3-(4-bromophenyl)-2-methyl-trans-propenoyl)amino!ethyl urea

Step 1. Preparation of 3-(4-bromophenyl)-2-methyl-trans-propenoate.

To a magnetically stirred solution of 4-bromobenzaldehyde (10.2 g, 55.1mmol) in dry THF (125 mL) was added(carboethoxyethylidene)triphenylphosphorane (21.0 g, 57.9 mmol) in smallportions. The reaction was stirred for 18 h at ambient temperature undera nitrogen atmosphere. The reaction was concentrated under vacuum andtriturated with hexanes; the precipitated triphenylphosphine oxide wasremoved by filtration. The filtrate was concentrated under vacuum andthe resulting slurry purified by chromatography over silica gel (100 g)using 10% ethyl acetate:hexanes as the eluant to provide the ethyl esterof the desired trans-propenoate (17.6 g, 86%). Hydrolysis of the ester(17.6 g, 47.6 mmol) was achieved by exposure to aqueous lithiumhydroxide (200 mL of a 1M solution, 200 mmol) in 95% ethanol (200 mL)for 5 hours. The reaction solution was filtered and the filtrateacidified to pH<2 with aqueous 6N HCl to precipitate the acid as a whitesolid. The acid was collected by filtration, washed with water, andvacuum dried to provide the title compound (11.5 g, 99%).

Step 2. Preparation of N-Hydroxy-N-2-(3-(4-chlorophenoxy)phenyl)-3-methyl-trans-propenoyl)amino!ethyl urea.

The title compound was prepared by following the procedures in example51 but employing 3-(4-bromophenyl)-2-methyl-trans-propenoate in lieu of2-phenoxybenzoate. The title compound was obtained as a colorless solidafter chromatograaphic purification and recrystallization from ethylacetate/hexanes. mp 172.5-174° C.; ¹ H NMR (300 MHz, D₆ -DMSO) 9.31 (1H,s), 8.03 (1H, t, J=6 Hz), 7.60 (2H, d, J=8 Hz), 7.34 (2H, d, J=8 Hz),7.16 (1H,br s), 6.32 (2H, s), 3.3-3.50 (4H, m), 1.98 (3H, d, J=1.5 Hz);MS (M+H)⁺ =342, (M+NH₄)⁺ =359. Analysis calc'd for C₁₃ H₁₆ N₃ O₃ Br: C,45.63 H, 4.71; N, 12.28; Found: C, 45.40; H, 4.55; N, 12.12.

EXAMPLE 166 Preparation of N-Hydroxy-N-2-(3-(4-chlorophenoxy)phenyl)-2-methyl-trans-propenoyl)amino!ethyl urea

The title compound was prepared by following the procedures in Example165 but employing 3-(4-chlorophenoxy)phenyl)-3-methyl-trans-propenoatein lieu of 3-(4-bromophenyl)-2-methyl-trans-propenoate. The titlecompound was obtained as a yellow solid after chromatographicpurification over silica gel using 50% ethyl acetate:hexanes as theeluant. ¹ H NMR (300 MHz, D₆ -DMSO) 9.30 (1H, s), 8.01 (1H, t, J=5.5Hz), 7.44 (2H, d, J=9 Hz), 7.43 (1H, m), 7.18 (1H, d, J=8 Hz), 7.05 (2H,d, J=9 Hz), 7.00 (2H, m), 6.54 (1H, m), 5.40 (2H, s), 3.55 (2H, m),3.27-3.34 (2H, m), 1.95 (3H, d, J=1.0 Hz). Analysis calc'd for C₁₂ H₂₀N₃ O₄ Cl: C, 47.14; H, 6.59; N, 13.74; Found: C, 46.90; H, 6.40; N,13.52.

EXAMPLE 167 Preparation of N-Hydroxy-N-2-(2-(3-(4-ethyloxyphenoxy)phenyl)-trans-cyclopropyl)carbonyl amino!ethylurea

The title compound was prepared by following the procedures in example 2but employing2-(3-(4-ethyloxyphenoxy)phenyl)-trans-cyclopropyl)carboxylic acid(prepared by oxidation of the corresponding aldehyde prepared asdescribed in Brooks, D. W.; Rodriques, K. E. U.S. Pat. No. 5,037,853) inlieu of 3-phenoxybenzoate. The title compound was obtained as acolorless solid after recrystallization from ethyl acetate and methanol.mp 173-175° C. (with decomposition); ¹ H NMR (300 MHz, D₆ -DMSO) 9.27(1H, s), 8.14 (1H, t, J=7 Hz), 7.22 (1H, t, J=8 Hz), 6.95 (4H, m), 6.82(1H, d, J=8 Hz), 6.72 (1H, s), 6.67 (1H, dd, J=8,1.5 Hz), 6.31 (1H, brs), 4.00 (2H, q, J=8 Hz), 3.32-3.40 (2H, m), 3.20-3.30 (2H, m),2.17-2.50 (1H, m), 1.83 (1H, dt, J=8.5, 5,5 Hz), 1.32 (3H,t, J=7.5 Hz),1.12-1.2 (1H, m); MS (M+H)⁺ =400. Analysis calc'd for C₂₁ H₂₅ N₃ O₅(0.25 H₂ O): C, 62.44; H, 6.36; N, 10.40; Found: C, 62.52; H, 6.39; N,10.36.

EXAMPLE 168 Preparation of N-Hydroxy-N-N"-(3-phenoxybenzoyl)aminomethyl!urea

Step 1: Preparation of N-(3-phenoxybenzoyl)aminomethanol

A flask was charged with 3-phenoxybenzoylamide (2.07 g, 9.8mmol)(prepared from the corresponding acid chloride and concentratedammonia), potassium carbonate (1.3 mL, 4% aqueous solution, 3.8 mmol),and aqueous formaldehyde (1.1 mL, 37% aqueous solution, 13.6 mmol). Theresulting suspension was heated to reflux to give a two-phased solution.Addition of more aqueous formaldehyde (3 mL, 37 mmol) gave a homogeneoussolution which was heated at reflux for 4 h. The reaction solution wascooled and partitioned between brine and ethyl acetate. The aqueouslayer was dram off and extracted with ethyl acetate (2×). The combinedorganic layers were washed (2×, brine), dried (Na₂ SO₄), andconcentrated under vacuum to provide 2.47 gms of a viscous oil whichsolidified after vacuum drying. Recrystallization from cold ethylacetate:hexanes provided the title compound as a colorless solid (1.38g, 58%), mp 112.5-113° C.

Step 2. Preparation of N-Hydroxy-N-N"-(3-phenoxybenzoyl)aminomethyl!urea.

To an ice-cooled solution of N-((3-phenoxy)benzoyl)aminomethanol (0.50g, 2.06 mmol), N,O-diphenoxycarbonylhydroxylamine (0.62 g, 2.26 mmol),and triphenylphosphine (0.59 g, 2.26 mmol) in dry THF (5 mL) was addeddiethylazodicarboxylate (356 μL, 2.26 mmol) in dry (THF). After theaddition was complete the cooling bath was removed and the reactionstirred at ambient temperature for 1 h. The volatiles were removed undervacuum and the resulting slurry was dissoved in 15 mL of dichloromethaneand concentrated under vacuum (2 cycles) and purified by chromatography(silica gel, 20% ethyl acetate/hexanes, column packed with hexanes) toprovide the corresponding mitsunobu product as an oil. (0.64 g, 62%).The mitsunobu product (0.60 g, 1.2 mmol) was exposed to concentratedammonoim hydroxide (3 mL) in dioxane (1 mL) and methanol (1 mL) for 4 hand concentrated under vacuum. The resulting slurry was purified bychromatography (silica gel, packed in dichlormethane, eluted with 5%methanol:chloroform) to provide the title compound and minorcontaminants. Recrystallization from ethyl actate:methanol provided thepure title compound as a colorless solid. m.p. 151°-154° C. (softeningat ˜120° C.); ¹ H NMR (300 MHz, D₆ -DMSO; the HNMR was a mixture of tworotamers which were evident in some of the absorptions) 9.37 (1H, s),9.04 and 8.87 (1H, t, J=6 Hz), 7.65-7.70 (1H, m), 7.39-7.53 (4H, m),7.15-7.21 (2H, m), 7.03 (2H, dq, J=8.5,1,1,1 Hz), 6.67 and 6.38 (2H, s),5.03 and 4.91 (2H, d, J=6 Hz); MS (M+H)⁺ =302, (M+NH₄)⁺ =319. Analysiscalc'd for C₁₅ H₁₅ N₃ O₄ (0.30 H₂ O): C, 58.75; H, 5.13; N, 13.70;Found: C, 58.52; H, 4.89; N, 14.40.

EXAMPLE 169 Preparation of (S)-N-Hydroxy-N-2-((2-(3-phenoxyphenyloxy)acetyl)amino)propyl!urea

Step 1: Preparation of 2-(3-phenoxyphenyloxy)acetate.

To a flask charged with reagent grade acetone (400 mL) was added3-phenoxyphenol (10.0 g, 52.6 mmol), potassium carbonate (7.6 g, 55mmol), and ethyl bromoacetate (6.1 mL, 53.7 mmol). The resulting mixturewas stirred at ambient temperature for 20 h, concentrated under vacuumto ˜50 mL, and partitioned between ethyl acetate and water. Afterseparating the two layers the aqueous solution was extracted with ethylacetate (2×). The combined organic layers were washed (2×, brine), dried(MgSO₄), and concentrated under vacuum to provide the ethyl ester of thetitle compound (14.35 g, 100%). The ester was hydrolyzed without furtherpurification by exposure to excess aqueous lithium hydroxide (200 mL, 1MLiOH), in ethanol (200 mL) for 4 h at ambient temperature. The reactionsolution was acidified with excess aqueous 2N HCL, and extracted withethyl acetate (2×). The combined organic layers were concentrated undervacuum and the resulting gummy liquid azeotroped with toluene (2×) toremove water. The resulting viscous green oil was recrystallized fromether:pentane at -20° C. to provide the title acid as a coilorlesssolid.

Step 2: Preparation of (S)-N-Hydroxy-N-2-((2-(3-phenoxyphenyloxy)acetyl)amino)ethyl!urea.

The title compound was prepared as described in example 51 but employing2-(3-phenoxyphenyloxy)acetate and (S)-N-hydroxy-N-2-((tert-butoxycarbonyl)amino)propyl!urea in lieu of 2-phenoxybezoicacid and N-hydroxy-N- 2-((tert-butoxycarbonyl) amino)ethyl!urea.Chromatographic purification (silica gel, 4% methanol/ether/hexanes) andrecrystallization from ether/methanol at -20° C. provided the titlecompound as a colorless solid (0.31 g, 25%). m.p. 137°-138° C.; ¹ H NMR(300 MHz, D₆ -DMSO) 9.32 (1H, s), 7.98 (1H, d, J=8 Hz), 7.40 (2H, dd,J=9,8 Hz), 7.28 (1H, t, J=8.5 Hz), 7.14 (1H, t, J=8.5 Hz), 7.03 (2H, d,J=9 Hz), 6.73 (1H, dd, J=9,2 Hz), 6.57-6.63 (2H, m), 6.30 (2H, s), 4.42(2H, s), 4.12 (1H, septet, J=6.5 Hz), 3.25-3.48 (4H, m), 1.04 (3H, d,J=6.5 Hz); MS (M+H)⁺ =360. Analysis calc'd for C₁₈ H₂₁ N₃ OS: C, 60.16;H, 5.89; N, 11.69; Found: C, 60.02; H, 5.97; N, 11.42.

EXAMPLE 170 Preparation of N-Hydroxy-N-2-((2-(3-phenoxyphenyloxy)propionyl)amino)ethyl!urea

Step 1: Preparation of 2-(3-phenoxyphenyloxy)propionate

The title compound was prepared as described in Example 169 butemploying methyl 2-bromopropionate in lieu of ethyl bromoacetate toprovide the title compound as a colorless solid (mp 70°-73.5° C.).

Step 2: Preparation of N-Hydroxy-N-2-((2-(3-phenoxyphenyloxy)propionyl)amino)ethyl!urea.

The title compound was prepared as described in example 51 but employing2-(3-phenoxyphenyloxy)propionate in lieu of 2-phenoxybezoic acid.Chromatographic purification (silica gel, 4% methanol/dichloromethane)and recrystallization from ether/ethyl acetate at -20° C. provided thetitle compound as a colorless solid (0.61 g, 22%). m.p. 112°-113° C.; ¹H NMR (300 MHz, D₆ -DMSO) 9.27 (1H, s), 8.07 (1H, d, J=8 Hz), 7.39 (2H,dd, J=9,8 Hz), 7.28 (1H, t, J=8.5 Hz), 7.14 (1H, t, J=8.5 Hz), 7.02 (2H,d, J=9 Hz), 6.68 (1H, dd, J=9,2 Hz), 6.53-6.60 (2H, m), 6.31 (2H, s),4.66 (1H, q, J=6.5 Hz), 3.18-3.48 (4H, m), 1.39 (3H, d, J=6.5 Hz); MS(M+H)⁺ =360, (M+NH₄)⁺ =388. Analysis calc'd for C₁₈ H₂₁ N₃ O₅ : C,60.16; H, 5.89; N, 11.69; Found: C, 60.06; H, 5.88; N, 11.68.

EXAMPLE 171 Preparation of (d,l)-N-Hydroxy-N-3-(2-(3-(4-chlorophenoxy)phenyl)acetylamino)prop-2-yl!urea

Step 1: Preparation of (3-(4-chlorophenoxy)phenyl)methylcyanide

To an ice-cooled flask charged with dichloromethane (50 mL) and3-(4-chlorophenoxy)benzyl alcohol (2.97 g, 12.7 mmol) was addedphosphorous tribromide (15 mL, 1M solution in dichloromethane, 15 mmlo).The resulting solution was stirred at ambient temperature for 17 h andcrushed ice added, and the two-phased mixture was extracted with ether(3×, 100 mL) The combined organic layers were washed (2×, brine), dried(MgSO₄), and concentrated under vacuum to provide the unpurified benzylbromide which was carried on without further purification. The benzylbromide and sodium cyanide (1.0 g, 20.4 mmol) were dissolved in DMSO andstirred at ambient temperature for 1 h. The reaction mixture waspartitioned between brine and ethyl acetate and the aqueous layer wasextracted again (2×, ethyl acetate). The combined organic layers weredried (MgSO₄) and concentrated under vacuum. The resulting oil waspurified by chromatography (silica gel, 20% ethyl acetate/hexanes) togive the pure cyano derivative (1.12 g, 36%).

Step 2: Preparation of 2-(3-(4-chlorophenoxy)phenyl)acetate

The cyanide (2.0 g, 8.21 mmol) prepared in step 1 was hydrolyzed to thecorresponding acid according to the procedure of Adams (Org. Synth.,Coll Vol. I., Gilman, H.; Blatt, A. H.: eds.; John Wiley & Sons; NewYork, 1976; p 436) by refluxing with water, sulfuric acid, and aceticacid. Recrystallization of the unpurified acid from ether provided thetitle compound as light tan crystals (1.05 g, 49%).

Step 3: Preparation of (d,l)-N-Hydroxy-N-3-(2-(3-(4-chlorophenoxy)phenyl)acetylamino)prop-2-yl!urea

The title compound was prepared as described in example 51 but employing2-(3-(4-chlorophenoxy)phenyl)acetate and (d,l)-N-Hydroxy-N-3-((tert-butyoxycarbonyl) amino)prop-2-yl!urea in lieu of2-phenoxybezoic acid and N-hydroxy-N- 2-((tert-butoxycarbonyl)amino)ethyl!urea. Recrystallization from ethyl acetate/hexanes providedthe title compound as a colorless solid (0.12 g, 35%). m.p. 161°-162.5°C.; ¹ H NMR (300 MHz, D₆ -DMSO) 9.32 (1H, s), 8.03 (1H, d, J=8 Hz), 7.43(2H, dt, J=9,1.5 Hz), 7.23 (1H, t, J=8.5 Hz), 7.00-7.09 (3H, m), 6.94(1H, br s), 6.89 (1H, dd, J=9,2 Hz), 6.29 (2H, s), 4.12 (1H, septet,J=6.5 Hz), 3.42 (2H, s), 3.00-3.18 (2H, m), 0.90 (3H, d, J=6.5 Hz); MS(M+H)⁺ =378/380. Analysis calc'd for C₁₈ H₂₀ N₃ O₄ Cl(0.5 H₂ O): C,55.96; H, 5.14; N, 10.70; Found: C, 55.89; H, 5.47; N, 10.86.

EXAMPLE 172 Preparation of N-Hydroxy-N-3-((3-(3-(4-chlorophenoxy)phenyl)propionyl)amino)prop-2-yl!urea

Following the procedure outlined in example 51 but employing3-(3-(4-chlorophenoxy)phenyl)propionyl chloride (prepared by reductionof 3-(3-(4-chlorophenoxy)phenyl)propenoic acid over 5% Pt/C in ethylacetate at 4 atm of hydrogen and subsequent conversion to the acidchloride with oxalyl chloride) and (d,l)-N-Hydroxy-N-3-((ten-butyoxycarbonyl)amino)prop-2-yl!urea in lieu of 2-phenoxybenzoylchloride and N-hydroxy-N- 2-((tert-butoxycarbonyl) amino)ethyl!ureaprovided the title compound as a colorless solid after recrystallizationfrom methanol. m.p. 161°-163° C.; ¹ H NMR (300 MHz, D₆ -DMSO) 8.79 (1H,s), 7.88 (1H, t, J=5.5,5.5 Hz), 7.43 (2H, d, J=8.5 Hz), 7.29 (1H, d,J=8.5 Hz), 7.02 (2H, d, J=8.5 Hz), 6.88 (1H, br s), 6.84 (1H, d,d,J=8.5,2 Hz), 6.28 (2H, s), 4.08 (1H, septet, J=7 Hz), 3.03-3.10 (2H, m),2.80 (2H, t, J=7.5 Hz), 2.38 (2H, t, J=7.5 Hz), 0.89 (3H, d, J=7 Hz),;MS (M+H)⁺ =392. Analysis calc'd for C₁₉ H₂₂ N₃ O₄ Cl(0.75 H₂ O): C,57.58; H, 5.72; N, 10.00; Found: C, 57.43; H, 5.46; N, 10.22.

EXAMPLE 173 Preparation of N-Hydroxy-N-5-(3-phenoxybenzoyl)amino!-pent-3-yn-2-yl urea

Step 1: Preparation of (3-phenoxybenzoyl)amino-2-propyne.

To a dichloromethane (25 mL) solution of amino-2-propyne (0.96 g, 17.43mmol) and triethylamine (3.33 mL, 23.7 mmol) at 0° C. was added3-phenoxybenzoyl chloride (3.68 g, 15.8 mmol) in dichloromethane (25 mL)in a dropwise fashion. The reaction was stirred for 1 h after removingthe cooling bath and partitioned between dichloromethane and 10% aqueousHCl. The layers were separated and the aqueous layer was extracted withdichloromethane (2×). The combined organic layers were washed (1×,saturated sodium bicarbonate; 1×, brine), dried (MgSO₄), andconcentrated under vacuum to give a golden oil. Recrystallization withehter ethyl acetate provided the title compound as a colorless solid(2.95 g, 74%).

Step 2: Preparation of 5-(3-phenoxybenzoyl)amino-3-propyn-2-ol

A solution of (3-phenoxy benzoyl)amino-2-propyne (2.54 g, 10.1 mmol) indry THF (30 mL) was cooled to -78° C. and n-butyl lithium (8.9 mL, 2.5Msolution in hexanes, 22.4 mmol) added via syringe. Acetaldehyde wasadded via syringe in a single portion to the red reaction solution.After stirring for 10 min at -78° C., the reaction was quenched byadding excess saturated ammonium chloride and partitioned between waterand ethyl acetate. The aqueous layer was extracted a second time and thecombined organic layers were washed (1×, saturated sodium bicarbonate;1×, brine), dried (MgSO₄), and concentrated under vacuum to provide alight yellow oil. Purification by chromatography (silica gel, 30% ethylacetate/hexanes) to provide the title compound as a colorless oil (1.05g, 35%).

Step 3: Preparation of N-Hydroxy-N-5-(3-phenoxybenzoyl)amino!-pent-3,yn-2-yl urea.

The title compound was prepared as described for the conversion ofN-Boc-1-amino-2-propanol to (d,l)-N-Hydroxy-N-3-((tert-butyoxycarbonyl)amino)prop-2-yl!urea using5-(3-phenoxybenzoyl)amino-3-propyn-2-ol in lieu ofN-Boc-1-amino-2-propanol. The purified product was obtained afterchromatography (silica gel, 3% methanol/dichloromethane) as a colorlessfoam. m.p. 63°-85° C. (shrinking and melting observed over the entirerange); ¹ H NMR (300 MHz, D₆ -DMSO) 9.23 (1H, s),8.67 (1H, t, J=6 Hz),7.20-7.32 (4H, m), 7.16 (1H, d, J=4.5 Hz), 6.47 (2H, s), 5.82 (1H, d,J=4.5 Hz), 4.91 (1H, br q, J=7 Hz), 3.98 (2H, dd, J=6,1.5 Hz), 1.24 (3H,d, J=7 Hz); MS (M+H)⁺ =362, (M+NH₄)⁺ =379.

The substituted amide-linked N-hydroxyurea compounds of Examples 174-253as shown in Table 45 are prepared by the method used for Example 2substituting m-phenoxybenzoic acid with the requisite substitutedmercaptobenzoic acid derivative which can be prepared by alkylation ofthe corresponding mercaptobenzoate according to the procedure describedin example 23 for the alkylation of 3-hydroxybenzoate.

                  TABLE 5    ______________________________________    Novel Substituted Mercaptobenzoate    Amide-linked N-Hydroxyureas     ##STR11##    Example     n     R.sub.1    ______________________________________    174         0     (CH.sub.2).sub.2 CH.sub.3    175         2     (CH.sub.2).sub.2 CH.sub.3    176         0     (CH.sub.2).sub.3 CH.sub.3    177         2     (CH.sub.2).sub.3 CH.sub.3    178         0     (CH.sub.2).sub.4 CH.sub.3    179         2     (CH.sub.2).sub.4 CH.sub.3    180         0     (CH.sub.2).sub.5 CH.sub.3    181         2     (CH.sub.2).sub.5 CH.sub.3    182         0     CH.sub.2 CH(CH.sub.3).sub.2    183         2     CH.sub.2 CH(CH.sub.3).sub.2    184         0     (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    185         2     (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    186         0     (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    187         2     (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    188         0     (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    189         2     (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    190         0     CH.sub.2 CHCH.sub.2    191         2     CH.sub.2 CHCH.sub.2    192         0    trans-CH.sub.2 CHCHCH.sub.3    193         2    trans-CH.sub.2 CHCHCH.sub.3    194         0    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    195         2    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    196         0     CH.sub.2 CHC(CH.sub.3)CH.sub.3    197         2     CH.sub.2 CHC(CH.sub.3)CH.sub.3    198         0     CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    199         2     CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    200         0     CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    201         2     CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    202         0     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    203         2     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    204         0     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    205         2     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    206         0     CH.sub.2 -2-pyridyl    207         2     CH.sub.2 -2-pyridyl    208         0     CH.sub.2 -3-pyridyl    209         2     CH.sub.2 -3-pyridyl    210         0     CH.sub.2 -4-pyridyl    211         2     CH.sub.2 -4-pyridyl    212         0     CH.sub.2 -2-furyl    213         2     CH.sub.2 -2-furyl    214         0     CH.sub.2 -3-furyl    215         2     CH.sub.2 -3-furyl    216         0     CH.sub.2 -2-thienyl    217         2     CH.sub.2 -2-thienyl    218         0     CH.sub.2 -3-thienyl    219         2     CH.sub.2 -3-thienyl    220         0     CH.sub.2 -2-benzo b!thienyl    221         2     CH.sub.2 -2-benzo b!thienyl    222         0     CH.sub.2 -2-benzo b!furyl    223         2     CH.sub.2 -2-benzo b!furyl    224         0     CH.sub.2 -2-thiazoyl    225         2     CH.sub.2 -2-thiazoyl    226         0     CH.sub.2 -2-imidazoyl    227         2     CH.sub.2 -2-imidazoyl    228         0     CH(CH.sub.3)-2-pyrimidyl    229         2     CH(CH.sub.3)-2-pyrimidyl    230         0     CH(CH.sub.3)-2-pyridyl    231         2     CH(CH.sub.3)-2-pyridyl    232         0     CH(CH.sub.3)-3-pyridyl    233         2     CH(CH.sub.3)-3-pyridyl    234         0     CH(CH.sub.3)-4-pyridyl    235         2     CH(CH.sub.3)-4-pyridyl    236         0     CH(CH.sub.3).sub.2 -2-furyl    237         2     CH(CH.sub.3).sub.2 -2-furyl    238         0     CH(CH.sub.3)-3-furyl    239         2     CH(CH.sub.3)-3-furyl    240         0     CH(CH.sub.3)-2-thienyl    241         2     CH(CH.sub.3)-2-thienyl    242         0     CH(CH.sub.3)-3-thienyl    243         2     CH(CH.sub.3)-3-thienyl    244         0     CH(CH.sub.3)-2-benzo b!thienyl    245         2     CH(CH.sub.3)-2-benzo b!thienyl    246         0     CH(CH.sub.3).sub.2 -2-benzo b!furyl    247         2     CH(CH.sub.3).sub.2 -2-benzo b!furyl    248         0     CH(CH.sub.3)-2-thiazoyl    249         2     CH(CH.sub.3)-2-thiazoyl    250         0     CH(CH.sub.3)-2-imidazoyl    251         2     CH(CH.sub.3)-2-imidazoyl    252         0     CH(CH.sub.3)-2-pyrimidyl    253         2     CH(CH.sub.3)-2-pyrimidyl    ______________________________________

The substituted amide-linked N-hydroxyurea compounds of Examples 254-293as shown in Table 6 are prepared by the method used for Example 2substituting m-phenoxybenzoic acid with the requisite substitutedaminobenzoic acid derivative which can be prepared by routine alkylativemethodology for anilines.

                  TABLE 6    ______________________________________    Substituted Aminobenzoate Amide-linked N-Hydroxyureas     ##STR12##    Example    R1    ______________________________________    254        (CH.sub.2).sub.2 CH.sub.3    255        (CH.sub.2).sub.3 CH.sub.3    256        (CH.sub.2).sub.4 CH.sub.3    257        (CH.sub.2).sub.5 CH.sub.3    258        CH.sub.2 CH(CH.sub.3).sub.2    259        (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    260        (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    261        (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    262        CH.sub.2 CHCH.sub.2    263    trans-CH.sub.2 CHCHCH.sub.3    264    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    265        CH.sub.2 CHC(CH.sub.3)CH.sub.3    266        CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    267        CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    268        (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    269        (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    270        CH.sub.2 -2-pyridyl    271        CH.sub.2 -3-pyridyl    272        CH.sub.2 -4-pyridyl    273        CH.sub.2 -2-furyl    274        CH.sub.2 -3-furyl    275        CH.sub.2 -2-thienyl    276        CH.sub.2 -3-thienyl    277        CH.sub.2 -2-benzo b!thienyl    278        CH.sub.2 -2-benzo b!furyl    279        CH.sub.2 -2-thiazoyl    280        CH.sub.2 -2-imidazoyl    281        CH(CH.sub.3)-2-pyrimidyl    282        CH(CH.sub.3)-2-pyridyl    283        CH(CH.sub.3)-3-pyridyl    284        CH(CH.sub.3)-4-pyridyl    285        CH(CH.sub.3).sub.2 -2-furyl    286        CH(CH.sub.3)-3-furyl    287        CH(CH.sub.3)-2-thienyl    288        CH(CH.sub.3)-3-thienyl    289        CH(CH.sub.3)-2-benzo b!thienyl    290        CH(CH.sub.3).sub.2 -2-benzo b!furyl    291        CH(CH.sub.3)-2-thiazoyl    292        CH(CH.sub.3)-2-imidazoyl    293        CH(CH.sub.3)-2-pyrimidyl    ______________________________________

The substituted amide-linked N-hydroxyurea compounds of Examples 294-373shown in Table 7 are prepared by the method used for Example 2substituting m-phenoxybenzoic acid with the requisite substitutedfuranoic acid derivative which can be prepared according to thesubstitution procedure outlined in example 40.

                  TABLE 7    ______________________________________    Substituted Hydroxybenzoate Amide-linked N-Hydroxyureas     ##STR13##    Example     X     R.sub.1    ______________________________________    294         O     (CH.sub.2).sub.2 CH.sub.3    294         S     (CH.sub.2).sub.2 CH.sub.3    296         O     (CH.sub.2).sub.3 CH.sub.3    297         S     (CH.sub.2).sub.3 CH.sub.3    298         O     (CH.sub.2).sub.4 CH.sub.3    299         S     (CH.sub.2).sub.4 CH.sub.3    300         O     (CH.sub.2).sub.5 CH.sub.3    301         S     (CH.sub.2).sub.5 CH.sub.3    302         O     CH.sub.2 CH(CH.sub.3).sub.2    303         S     CH.sub.2 CH(CH.sub.3).sub.2    304         O     (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    305         S     (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    306         O     (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    307         S     (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    308         O     (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    309         S     (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    310         O     CH.sub.2 CHCH.sub.2    311         S     CH.sub.2 CHCH.sub.2    312         O    trans-CH.sub.2 CHCHCH.sub.3    313         S    trans-CH.sub.2 CHCHCH.sub.3    314         O    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    315         S    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    316         O     CH.sub.2 CHC(CH.sub.3)CH.sub.3    317         S     CH.sub.2 CHC(CH.sub.3)CH.sub.3    318         O     CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    319         S     CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    320         O     CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    321         S     CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    322         O     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    323         S     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    324         O     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    325         S     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    326         O     CH.sub.2 -2-pyridyl    327         S     CH.sub.2 -2-pyridyl    328         O     CH.sub.2 -3-pyridyl    329         S     CH.sub.2 -3-pyridyl    330         O     CH.sub.2 -4-pyridyl    331         S     CH.sub.2 -4-pyridyl    332         O     CH.sub.2 -2-furyl    333         S     CH.sub.2 -2-furyl    334         O     CH.sub.2 -3-furyl    335         S     CH.sub.2 -3-furyl    336         O     CH.sub.2 -2-thienyl    337         S     CH.sub.2 -2-thienyl    338         O     CH.sub.2 -3-thienyl    339         S     CH.sub.2 -3-thienyl    340         O     CH.sub.2 -2-benzo b!thienyl    341         S     CH.sub.2 -2-benzo b!thienyl    342         O     CH.sub.2 -2-benzo b!furyl    343         S     CH.sub.2 -2-benzo b!furyl    344         O     CH.sub.2 -2-thiazoyl    345         S     CH.sub.2 -2-thiazoyl    346         O     CH.sub.2 -2-imidazoyl    347         S     CH.sub.2 -2-imidazoyl    348         O     CH(CH.sub.3)-2-pyrimidyl    349         S     CH(CH.sub.3)-2-pyrimidyl    350         O     CH(CH.sub.3)-2-pyridyl    351         S     CH(CH.sub.3)-2-pyridyl    351         O     CH(CH.sub.3)-3-pyridyl    353         S     CH(CH.sub.3)-3-pyridyl    354         O     CH(CH.sub.3)-4-pyridyl    355         S     CH(CH.sub.3)-4-pyridyl    356         O     CH(CH.sub.3).sub.2 -2-furyl    357         S     CH(CH.sub.3).sub.2 -2-furyl    358         O     CH(CH.sub.3)-3-furyl    359         S     CH(CH.sub.3)-3-furyl    360         O     CH(CH.sub.3)-2-thienyl    361         S     CH(CH.sub.3)-2-thienyl    362         O     CH(CH.sub.3)-3-thienyl    363         S     CH(CH.sub.3)-3-thienyl    364         O     CH(CH.sub.3)-2-benzo b!thienyl    365         S     CH(CH.sub.3)-2-benzo b!thienyl    366         O     CH(CH.sub.3).sub.2 -2-benzo b!furyl    367         S     CH(CH.sub.3).sub.2 -2-benzo b!furyl    368         O     CH(CH.sub.3)-2-thiazoyl    369         S     CH(CH.sub.3)-2-thiazoyl    370         O     CH(CH.sub.3)-2-imidazoyl    371         S     CH(CH.sub.3)-2-imidazoyl    372         O     CH(CH.sub.3)-2-pyrimidyl    373         S     CH(CH.sub.3)-2-pyrimidyl    ______________________________________

The substituted amide-linked N-hydroxyurea compounds of Examples 374-384as shown in Table 8 are prepared by the method used for Example 57substituting m-phenoxybenzoic acid with the requisite substitutedbenzoic acid derivative and by employing the procedure from example 57while employing the products from examples 48, 49, or by synthesis ofother analogues derived from natural and unnatural amino acids followingthe procedures in example 48.

                  TABLE 8    ______________________________________    Substituted Phenoxybenzoate Amide-linked N-Hydroxyureas     ##STR14##    Example      R.sub.4    ______________________________________    374          (S)-Me    375          (R)-Me    376          (S)-Et    377          (R)-Et    378          (R)-n-Pr    379          (R)-i-Pr    380          (R)-i-Bu    381          (R)-n-Bu    382          (R)-CH.sub.2 Ph    383          (R)-CH.sub.2 OH    384          (R)-(CH.sub.2).sub.4 NH.sub.2    ______________________________________

The substituted amide-linked N-hydroxyurea compounds of Examples 385-428shown in Table 9 are prepared by the method used for Example 1substituting m-phenoxyaniline with the requisite substituted ortho-,meta-, or para-hydroxyaniline derivative which can be prepared accordingto the alkylation procedure outlined in example 23 utilizingN-Boc-hydroxyanilines in lieu of hydroxybenzoate.

                  TABLE 9    ______________________________________    Substituted Hydroxyaniline Amide-linked N-Hydroxyureas     ##STR15##    Example    R.sub.1    ______________________________________    385        CH.sub.2 CH.sub.3    386        (CH.sub.2).sub.2 CH.sub.3    387        (CH.sub.2).sub.3 CH.sub.3    388        (CH.sub.2).sub.4 CH.sub.3    389        (CH.sub.2).sub.5 CH.sub.3    390        CH.sub.2 CH(CH.sub.3).sub.2    391        (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    392        (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    393        (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    394        CH.sub.2 CHCH.sub.2    395    trans-CH.sub.2 CHCHCH.sub.3    396    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    397        CH.sub.2 CHC(CH.sub.3)CH.sub.3    398        CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    399        CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    400        (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    401        (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    402        CH.sub.2 -2-pyridyl    403        CH.sub.2 -3-pyridyl    404        CH.sub.2 -4-pyridyl    405        CH.sub.2 -2-furyl    406        CH.sub.2 -3-furyl    407        CH.sub.2 -2-thienyl    408        CH.sub.2 -3-thienyl    409        CH.sub.2 -2-benzo b!thienyl    410        CH.sub.2 -2-benzo b!furyl    411        CH.sub.2 -2-thiazoyl    412        CH.sub.2 -2-imidazoyl    413        CH(CH.sub.3)-2-pyrimidyl    414        CH(CH.sub.3)-2-pyridyl    415        CH(CH.sub.3)-3-pyridyl    416        CH(CH.sub.3)-4-pyridyl    417        CH(CH.sub.3).sub.2 -2-furyl    418        CH(CH.sub.3)-3-furyl    419        CH(CH.sub.3)-2-thienyl    420        CH(CH.sub.3)-3-thienyl    421        CH(CH.sub.3)-2-benzo b!thienyl    422        CH(CH.sub.3).sub.2 -2-benzo b!furyl    423        CH(CH.sub.3)-2-thiazoyl    424        CH(CH.sub.3)-2-imidazoyl    425        CH(CH.sub.3)-2-pyrimidyl    426    2-pyridyl    427    3-pyridyl    428    4-pyridyl    ______________________________________

The substituted amide-linked N-hydroxyurea compounds of Examples 429-508as shown in Table 10 are prepared by the method used for Example 1substituting m-phenoxyaniline with the requisite substituted ortho-,meta-, or para-mercaptoaniline derivative which can be prepared byalkylation of the corresponding mercaptoaniline according to theprocedure described in example 23 for the alkylation of3-hydroxybenzoate but employing N-Boc-mercaptoaniline in lieu of3-hydroxybenzoate.

                  TABLE 10    ______________________________________    Substituted Mercaptoaniline Amide-linked N-Hydroxyureas     ##STR16##    Example     n     R.sub.1    ______________________________________    429         0     (CH.sub.2).sub.2 CH.sub.3    430         2     (CH.sub.2).sub.2 CH.sub.3    431         0     (CH.sub.2).sub.3 CH.sub.3    432         2     (CH.sub.2).sub.3 CH.sub.3    433         0     (CH.sub.2).sub.4 CH.sub.3    434         2     (CH.sub.2).sub.4 CH.sub.3    435         0     (CH.sub.2).sub.5 CH.sub.3    436         2     (CH.sub.2).sub.5 CH.sub.3    437         0     CH.sub.2 CH(CH.sub.3).sub.2    438         2     CH.sub.2 CH(CH.sub.3).sub.2    439         0     (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    440         2     (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    441         0     (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    442         2     (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    443         0     (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    444         2     (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    445         0     CH.sub.2 CHCH.sub.2    446         2     CH.sub.2 CHCH.sub.2    447         0    trans-CH.sub.2 CHCHCH.sub.3    448         2    trans-CH.sub.2 CHCHCH.sub.3    449         0    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    450         2    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    451         0     CH.sub.2 CHC(CH.sub.3)CH.sub.3    452         2     CH.sub.2 CHC(CH.sub.3)CH.sub.3    453         0     CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    454         2     CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    455         0     CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    456         2     CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    457         0     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    458         2     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    459         0     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    460         2     (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    461         0     CH.sub.2 -2-pyridyl    462         2     CH.sub.2 -2-pyridyl    463         0     CH.sub.2 -3-pyridyl    464         2     CH.sub.2 -3-pyridyl    465         0     CH.sub.2 -4-pyridyl    466         2     CH.sub.2 -4-pyridyl    467         0     CH.sub.2 -2-furyl    468         2     CH.sub.2 -2-furyl    469         0     CH.sub.2 -3-furyl    470         2     CH.sub.2 -3-furyl    471         0     CH.sub.2 -2-thienyl    472         2     CH.sub.2 -2-thienyl    473         0     CH.sub.2 -3-thienyl    474         2     CH.sub.2 -3-thienyl    475         0     CH.sub.2 -2-benzo b!thienyl    476         2     CH.sub.2 -2-benzo b!thienyl    477         0     CH.sub.2 -2-benzo b!furyl    478         2     CH.sub.2 -2-benzo b!furyl    479         0     CH.sub.2 -2-thiazoyl    480         2     CH.sub.2 -2-thiazoyl    481         0     CH.sub.2 -2-imidazoyl    482         2     CH.sub.2 -2-imidazoyl    483         0     CH(CH.sub.3)-2-pyrimidyl    484         2     CH(CH.sub.3)-2-pyrimidyl    485         0     CH(CH.sub.3)-2-pyridyl    486         2     CH(CH.sub.3)-2-pyridyl    487         0     CH(CH.sub.3)-3-pyridyl    488         2     CH(CH.sub.3)-3-pyridyl    489         0     CH(CH.sub.3)-4-pyridyl    490         2     CH(CH.sub.3)-4-pyridyl    491         0     CH(CH.sub.3).sub.2 -2-furyl    492         2     CH(CH.sub.3).sub.2 -2-furyl    493         0     CH(CH.sub.3)-3-furyl    494         2     CH(CH.sub.3)-3-furyl    495         0     CH(CH.sub.3)-2-thienyl    496         2     CH(CH.sub.3)-2-thienyl    497         0     CH(CH.sub.3)-3-thienyl    498         2     CH(CH.sub.3)-3-thienyl    499         0     CH(CH.sub.3)-2-benzo b!thienyl    500         2     CH(CH.sub.3)-2-benzo b!thienyl    501         0     CH(CH.sub.3).sub.2 -2-benzo b!furyl    502         2     CH(CH.sub.3).sub.2 -2-benzo b!furyl    503         0     CH(CH.sub.3)-2-thiazoyl    504         2     CH(CH.sub.3)-2-thiazoyl    505         0     CH(CH.sub.3)-2-imidazoyl    506         2     CH(CH.sub.3)-2-imidazoyl    507         0     CH(CH.sub.3)-2-pyrimidyl    508         2     CH(CH.sub.3)-2-pyrimidyl    ______________________________________

The substituted amide-linked N-hydroxyureas compounds of Examples509-548 as shown in Table 11 are prepared by the method used for Example1 substituting m-phenoxyaniline with the requisite substituted ortho-,meta-, or para-aminoaniline derivative which can be prepared by routinealkylative methodology for anilines.

                  TABLE 11    ______________________________________    Substituted Aminobenzoate Amide-linked N-Hydroxyureas     ##STR17##    Example    R1    ______________________________________    509        (CH.sub.2).sub.2 CH.sub.3    510        (CH.sub.2).sub.3 CH.sub.3    511        (CH.sub.2).sub.4 CH.sub.3    512        (CH.sub.2).sub.5 CH.sub.3    513        CH.sub.2 CH(CH.sub.3).sub.2    514        (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    515        (CH.sub.2).sub.3 CH(CH.sub.3).sub.2    516        (CH.sub.2).sub.4 CH(CH.sub.3).sub.2    517        CH.sub.2 CHCH.sub.2    518    trans-CH.sub.2 CHCHCH.sub.3    519    trans-CH.sub.2 C(CH.sub.3)CHCH.sub.3    520        CH.sub.2 CHC(CH.sub.3)CH.sub.3    521        CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2    522        CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    523        (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.3).sub.2    524        (CH.sub.2).sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2    525        CH.sub.2 -2-pyridyl    526        CH.sub.2 -3-pyridyl    527        CH.sub.2 -4-pyridyl    528        CH.sub.2 -2-furyl    529        CH.sub.2 -3-furyl    530        CH.sub.2 -2-thienyl    531        CH.sub.2 -3-thienyl    532        CH.sub.2 -2-benzo b!thienyl    533        CH.sub.2 -2-benzo b!furyl    534        CH.sub.2 -2-thiazoyl    535        CH.sub.2 -2-imidazoyl    536        CH(CH.sub.3)-2-pyrimidyl    537        CH(CH.sub.3)-2-pyridyl    538        CH(CH.sub.3)-3-pyridyl    539        CH(CH.sub.3)-4-pyridyl    540        CH(CH.sub.3).sub.2 -2-furyl    541        CH(CH.sub.3)-3-furyl    542        CH(CH.sub.3)-2-thienyl    543        CH(CH.sub.3)-3-thienyl    544        CH(CH.sub.3)-2-benzo b!thienyl    545        CH(CH.sub.3).sub.2 -2-benzo b!furyl    546        CH(CH.sub.3)-2-thiazoyl    547        CH(CH.sub.3)-2-imidazoyl    548        CH(CH.sub.3)-2-pyrimidyl    ______________________________________

The examples presented above are provided to enable one skilled in theart to practice the present invention and should not be read as limitingthe scope of the invention which is defined by the appended claims.

We claim:
 1. A compound having the structure ##STR18## or apharmaceutically acceptable salt thereof wherein R¹ is NR² R³ where R²and R³ are independently selected from hydrogen and alkyl of from one tosix carbon atoms;A is ##STR19## wherein R⁴ is selected from (a) phenoxy,optionally substituted with one, two, or three halogen atoms, alkyl offrom one to six carbon atoms, haloalkyl of from one to six carbon atoms,phenylalkoxy in which the alkoxy portion is of from one to six carbonatoms, and(b) thiophenoxy, optionally substituted with one, two, orthree halogen atoms, alkyl of from one to six carbon atoms, haloalkyl offrom one to six carbon atoms; Y is a valence bond or is selectedfromalkylene of from one to six carbon atoms, alkenylene of from two tosix carbon atoms, and oxyalkylene of from one to six carbon atoms; Z isoxygen or sulfur; B is ##STR20## wherein R⁹ is selected fromhydrogen,alkyl of from one to six carbon atoms, and D is straight orbranched chain alkylene of from one to six carbon atoms; and M ishydrogen or a pharmaceutically acceptable cation.
 2. A compound asdefined by claim 1 wherein D is (--CH₂ --)_(n) or ##STR21## wherein n is1, 2, or
 3. 3. A compound as defined by claim 1 selected from the groupconsisting ofN-hydroxy-N-2-((5-(4-methylphenoxy)furan-2-oyl)amino)ethyl!urea; N-hydroxy-N-2-((5-(4-chlorophenoxy)fur-2-oyl)amino)ethyl!urea; (R)-N-hydroxy-N-2-((5-(4-chlorophenoxy)fur-2-oyl)amino)propyl!urea; (S)-N-hydroxy-N-2-((5-(4-chlorophenoxy)fur-2-oyl)amino)propyl!urea; (R)-N-hydroxy-N-3-((5-(4-fluorophenoxy)furan-2-oyl)amino)prop-2-yl!urea;(S)-N-hydroxy-N- 3-((5-(4-fluorophenoxy)furan-2 -oyl)amino)prop-2yl!urea; (R)-N-hydroxy-N- 3-((5-(4-fluorothiophenoxy)furan-2-0yl)amino)prop-2-yl!urea; (S)-N-hydroxy-N-3-((5-(4-fluorothiophenoxy)furan-2-oyl)amino)prop-2-yl!urea;N-Hydroxy-N- 2-((5-(4-chlorophenoxy)fur-2-oyl)amino)ethyl!urea; andN-Hydroxy-N- 3-((5-(4-fluorophenoxy)furan-2-oyl)amino)prop-2-yl!urea;(R,S)-N-hydroxy-N-3-((5-(4-fluorophenoxy)furan-2-oyl)amino)prop-2-yl!urea;or apharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition for inhibiting the biosynthesis of leukotrienes comprising atherapeutically effective amount of a compound as defined by claim 1 incombination with a pharmaceutically acceptable carrier.
 5. A method ofinhibiting the biosynthesis of leukotrienes comprising administering toa mammal in need of such treatment a therapeutically effective amount ofa compound as defined by claim
 1. 6. A compound as defined by claim 1wherein Z is oxygen.
 7. A compound as defined by claim 1 wherein Z issulfur.